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Ongoing clinical trials of PD-1 and PD-L1 inhibitors for lung cancer in China

Si-Yang Liu and Yi-Long WuEmail author

Journal of Hematology & Oncology201710:136

https://doi.org/10.1186/s13045-017-0506-z

© The Author(s). 2017

Received: 7 April 2017

Accepted: 26 June 2017

Published: 5 July 2017
Abstract

Compared to chemotherapy, promising results have been obtained by blocking the PD-1 pathway using antibodies that inhibit programmed cell death protein 1 (PD-1) or programmed cell death protein ligand 1 (PD-L1). Furthermore, global researchers and doctors are exploring how to optimize this immunotherapy in 270 clinical studies. However, Chinese clinical trials of these agents remain in the early stages. We summarize the ongoing international and domestic clinical trials using PD-1 and PD-L1 inhibitors to treat lung cancer. This information can help researchers better understand the active and approved clinical trials in China, as well as the ongoing research regarding PD-1 and PD-L1 inhibitors.
Keywords
PD-1 inhibitor PD-L1 inhibitor Clinical trials China
Background

Immunotherapy is revolutionizing the treatment of multiple cancer types and provides promising clinical responses, durable disease control, and fewer adverse events among patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other tumor types [1]. Programmed cell death protein-1 (PD-1) is an important immune checkpoint protein that is expressing on the surface of T cells. When PD-1 binds to its ligands, such as programmed cell death protein ligand 1 (PD-L1) and programmed cell death protein ligand 2, T cell activity and cytokine production is greatly downregulated at the tumor site. This effect contrasts with the biological characteristics of treatments targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4), and PD-1/PD-L1 blockage is now considered a “tumor site immune modulation therapy” [2, 3]. Blocking the PD-1 pathway using monoclonal antibodies to PD-1 or PD-L1 can stimulate the patient’s immune system to kill tumor cells, and this approach has provided remarkable anti-tumor efficacy, compared to standard first-line and second-line chemotherapy for advanced NSCLC [4–8]. By the end of December 2016, the US Food and Drug Administration had approved PD-1 pathway blockade treatments using nivolumab, pembrolizumab, and atezolizumab [9].

In China, no PD-1 or PD-L1 inhibitors have received marketing approval from the Chinese Food and Drug Administration (CFDA). However, various clinical trials are actively investigating international and domestic drugs. Between January 1, 2013 and April 6, 2017, ClinicalTrials.gov registered 270 international clinical trials using PD-1/PD-L1 therapies for NSCLC (e.g., nivolumab, pembrolizumab, atezolizumab, and durvalumab). These 270 trials included 61 studies that involved East Asian sites and 14 studies that involved Chinese sites (12 multinational trials and 2 trials that only evaluated Chinese patients). Thus, research regarding immune checkpoint inhibitors in China is several years behind research in other areas of the world. This review evaluates the ongoing international and domestic clinical trials using PD-1 or PD-L1 inhibitors, and we hope this review will provide detailed information regarding how to perform immunotherapy clinical trials in China.
International trials
Chinese participation in international multicenter clinical trials using PD-1/PD-L1 inhibitors has greatly increased during the last 3 years. Based on our research, Chinese sites were involved in 14 global clinical trials by April 6, 2017. These trials included six first-line trials (NCT02220894 [KEYNOTE 042], NCT03003962, NCT02542293 [NEPTUNE], NCT02763579 [IMpower133], NCT02657434 [IMpower132], and NCT02409342 [IMpower110]), four second-line trials (NCT02864394 [MK-3475-033], NCT02613507 [CheckMate078], NCT02481830 [CheckMate331], and NCT02813785 [IMpower210]), two adjuvant therapy trials (NCT02486718 [IMpower010] and NCT02273375 [BR.31]), and two trials that only evaluated Chinese patients (NCT02835690 [KEYNOTE 032] and NCT02978482) (Fig. 1).
Fig. 1

Ongoing international clinical trials according to whether they included Chinese patients. a Between January 1, 2013, and April 6, 2017, there were 270 clinical trials of anti-PD-1/PD-L1 inhibitors for NSCLC that were registered on ClinicalTrials.gov. Among the 270 studies, 61 studies were performed in East Asia and 14 studies were performed in China (12 multinational trials and 2 trials that only evaluated Chinese patients). b The 14 clinical trials included six first-line studies, four second-line studies, two adjuvant therapy studies, and two phase I studies for only Chinese patients. c The classification of clinical trials in China according to the therapeutic agent, which includes nivolumab, pembrolizumab, atezolizumab, and durvalumab
First-line
Pembrolizumab (KEYNOTE 042)

KEYNOTE 042 was an international, open-label, randomized, phase III study that evaluated overall survival (OS) among treatment-naïve patients who received pembrolizumab (MK-3475) or platinum doublet chemotherapy for advanced or metastatic NSCLC. The KEYNOTE 024 trial enrolled patients with high PD-L1 expression (proportion score of ≥50%), while the KEYNOTE 042 trial evaluated patients with a PD-L1 tumor proportion score of ≥1% based on immunohistochemistry. Patients were excluded if their tumors harbored sensitive mutations in the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene. Participants were randomized 1:1 to receive either pembrolizumab monotherapy (200 mg every 3 weeks for up to 35 treatments or until disease progression) or carboplatin plus pemetrexed or paclitaxel (non-squamous tumor histology) for 4–6 cycles. The primary study hypothesis was that pembrolizumab would prolong OS compared to the chemotherapeutic standard of care (SoC). Thus, the primary endpoint was defined as OS and the secondary endpoint was defined as progression-free survival (PFS), which was evaluated by a central independent radiologist. This trial closed during February 2017 in China.
Durvalumab (NCT03003962)

The NCT03003962 trial is an open-label, multicenter, phase III study that is focused on Asian patients. Chinese hospitals account for 50% of the centers (16/32), and the study aims to enroll 440 patients with stage IV NSCLC, wild-type EGFR and ALK, and high PD-L1 expression (proportion score of ≥25%). These patients are randomized 1:1 to receive first-line treatment using either durvalumab (MEDI4736, a PD-1 inhibitor) or SoC platinum-based chemotherapy. The two primary objectives are to assess the treatment efficacies based on PFS and OS. The trial enrolled the first Chinese patients in February 2017 and will close in 2018.
Durvalumab (NEPTUNE)

Tremelimumab is an anti-CTLA4 antibody that may provide clinical benefits in patients with melanoma and some other tumors. However, it remains unclear whether a combination of two checkpoint inhibitors with completely different biological mechanisms can increase the patient response rates [2, 10]. The results of a phase I study using durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg) have been published in the Lancet Oncology [11] and revealed that this treatment provided manageable tolerability and anti-tumor activity, regardless of PD-L1 status. The NEPTUNE study is a global phase III study that compares platinum-based SoC chemotherapy to durvalumab plus tremelimumab immunotherapy for untreated patients with advanced or metastatic NSCLC and wild-type EGFR and ALK, regardless of their PD-L1 expression. Compared to the platinum-based SoC chemotherapy, the efficacy and safety of durvalumab will be evaluated in terms of OS. Patients are randomized 1:1 to the two treatment arms. The trial is currently recruiting patients and enrolled its first Chinese patient on February 4, 2017. The results will be released in 2018.
Atezolizumab (IMpower110)

The IMpower110 trial compares platinum plus pemetrexed (non-squamous disease) or gemcitabine (squamous disease) versus atezolizumab (MPDL3280A) among chemotherapy-naïve patients with stage IV NSCLC. The study considers both safety and efficacy outcomes. Patients with previously detected sensitizing EGFR mutations or ALK fusions may have received tyrosine kinase inhibitor treatment. Positive PD-L1 expression is determined using immunohistochemistry and a proportion score of ≥1%. This trial has not started recruiting patients in China.
Atezolizumab (IMpower133)

The clinical benefits and toxicities of combination immunotherapy for small cell lung cancer (SCLC) remain unclear, and several international clinical trials are ongoing [12]. The IMpower133 trial is a phase I/III, multicenter, double-blinded, placebo-controlled study that evaluates the safety and efficacy of atezolizumab (a PD-L1 inhibitor) with or without carboplatin plus etoposide. This study evaluates treatment-naïve patients with extensive-stage SCLC, who are randomized 1:1 to the two treatment arms. The induction phase is four 21-day cycles, and maintenance treatment using atezolizumab or placebo is provided until persistent radiographic disease progression or symptomatic deterioration is detected. This trial is currently recruiting patients in China and enrolled its first patient on April 2017. The estimated completion date is July 31, 2019.
Atezolizumab (IMpower132)
The IMpower132 trial is a randomized, phase III, multicenter, open-label study of patients who are chemotherapy-naïve and have stage IV non-squamous NSCLC. Patients are excluded if they have received prior treatment, a sensitizing EGFR mutation, or an ALK fusion oncogene. The primary outcome measures are PFS and OS to evaluate the safety and efficacy of atezolizumab in combination with cisplatin or carboplatin plus pemetrexed, and eligible patients will be randomized 1:1 into arm A (atezolizumab + carboplatin or cisplatin + pemetrexed) and or arm B (carboplatin or cisplatin + pemetrexed). The trial has not started recruiting patients (Table 1).
Table 1

Ongoing international clinical trials of PD-1 and PD-L1 inhibitors on lung cancer with participating Chinese centers

Indentifier


Drugs


Location(s)


Phase


Indication


Population


Status in China

NCT02220894

KEYNOTE 042


Pembrolizumab


International


III


First-line


Advanced or metastatic NSCLC, EGFR and ALK wild-type, PD-L1-positive


Closed

NCT03003962

−


Durvalumab


Asia (16/32)


III


First-line


Advanced NSCLC, EGFR and ALK wild-type, PD-L1-high expression


Recruiting

NCT02542293

NEPTUNE


Durvalumab

D + T


International


III


First-line


Advanced or metastatic, NSCLC, EGFR and ALK wild-type


Recruiting

NCT02409342

IMpower110


Atezolizumab


International


III


First-line


Chemotherapy-naïve and stage IV NSCLC, PD-L1-positive


Not yet recruiting

NCT02763579

IMpower133


Atezolizumab

A + C + E


International


I/III


First-line


Extensive-stage SCLC


Recruiting

NCT02657434

IMpower132


Atezolizumab

A + C + P


International


III


First-line


Chemotherapy-naïve and stage IV non-squamous NSCLC


Not yet recruiting

NCT02613507

CheckMate078


Nivolumab


Asia (23/32)


III


Second-line and beyond


Stage IIIB/IV or recurrent NSCLC after failure with platinum-containing doublet chemotherapy


Closed

NCT02864394

MK-3475-033


Pembrolizumab


International


III


Second-line and beyond


Stage IIIB/IV or recurrent NSCLC after failure with platinum-containing chemotherapy, PD-L1-positive, no EGFR sensitizing mutation


Recruiting

NCT02481830

CheckMate331


Nivolumab


International


III


Second-line


Relapsed SCLC after platinum-based first-line chemotherapy


Not yet recruiting

NCT02813785 IMpower 210


Atezolizumab


Asia (27/40)


III


Second-line and beyond


NSCLC after failure with platinum-containing chemotherapy


Recruiting

NCT02486718 IMpower 010


Atezolizumab


International


III


Adjuvant therapy


Stage IB–IIIA NSCLC following resection and adjuvant chemotherapy


Recruiting

NCT02273375

BR.31


Durvalumab


International


III


Adjuvant therapy


Completely resected stage IB–IIIA NSCLC


Recruiting

NCT02835690

KEYNOTE 032


Pembrolizumab


China


I


–


Locally advanced or metastatic NSCLC


Not yet recruiting

NCT02978482

–


Durvalumab

D + T


China


I


–


Advanced malignancies


Recruiting

NSCLC non-small cell lung cancer, EGFR epidermal growth factor receptor, ALK anaplastic lymphoma kinase, PD-L1 programmed cell death protein ligand 1, D + T durvalumab plus tremelimumab, A + C + E atezolizumab plus carboplatin plus etoposide
Second-line
Nivolumab (CheckMate078)

The Checkmate078 trial is the first Chinese study of a PD-1 inhibitor. This trial focused on Asian patients and aimed to enroll 500 patients with advanced or metastatic NSCLC who had failed platinum-based doublet chemotherapy. Chinese hospitals accounted for >70% of the centers (23/32). Patients were randomized 2:1 to receive either nivolumab (MDX-1106; 3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Patients with EGFR mutations were excluded, and ALK status was not considered. The primary outcome measure was OS. The trial has completed its recruitment, and the results will be released during 2017.
Pembrolizumab (MK-3475-033)

The study aims to assess the efficacies of pembrolizumab versus docetaxel among patients with stage IIIB/IV or recurrent NSCLC who have experienced disease progression after platinum-containing systemic therapy. Patients may not have an EGFR sensitizing mutation and must have positive PD-L1 expression (tumor proportion score of ≥1%) based on immunohistochemistry. The primary hypothesis of the study is that pembrolizumab will prolong OS and PFS, compared to docetaxel, among participants with PD-L1-positive tumors. The trial is recruiting patients in China, and the estimated study completion date is January 28, 2019.
Nivolumab (CheckMate 331)

Topotecan has been approved as a second-line treatment for SCLC but has provided disappointing efficacy. A phase I/II trial (CheckMate 032) revealed promising results from dual blockade of PD-1 and CTLA-4 for relapsed SCLC, compared with topotecan [13]. Thus, the phase III Checkmate 331 study compares nivolumab versus chemotherapy among patients with relapsed SCLC after failed platinum-based first-line chemotherapy. Patients are randomized to three treatment arms: the experimental arm with nivolumab, an active comparator arm with topotecan, and a second active comparator arm with amrubicin. Data from the ongoing phase III trial are needed to confirm whether nivolumab is effective for treating SCLC. This clinical trial has not started recruiting patients in China.
Atezolizumab (IMpower 210)

The IMpower 210 study is a multicenter, open-label, randomized controlled phase III study with sites in five East Asian countries. This study aims to evaluate the efficacy and safety of atezolizumab versus docetaxel among patients with locally advanced or metastatic NSCLC that has progressed during or after platinum-containing treatment. The study’s treatment will continue until disease progression or unacceptable toxicity is detected. The estimated enrollment is 563 patients, and the design targets 80% of the enrolled patients being recruited from 27 Chinese hospitals. Atezolizumab is administered at a fixed dose of 1200 mg using intravenous (IV) infusion on day 1 of each 21-day cycle. Docetaxel is administered as an IV infusion at a dose of 75 mg/m2 on day 1 of each 21-day cycle. The trial is currently recruiting patients in China, and the estimated study completion date is May 31, 2019.
Adjuvant therapy
Atezolizumab (IMpower 010)

The IMpower 010 study is a phase III, global, multicenter, open-label, randomized study to compare the efficacy and safety of 16 atezolizumab treatment cycles, compared to best supportive care, for patients with stage IB–IIIA NSCLC after resection and adjuvant chemotherapy. Participants will complete ≤4 cycles of adjuvant cisplatin-based chemotherapy and will then be randomized 1:1 to receive 16 cycles of atezolizumab treatment or best supportive care. The primary outcome is disease free survival (DFS), and the secondary outcome is OS. The IMpower010 study is currently recruiting patients in China, and the estimated study completion date is September 25, 2026.
Durvalumab (BR.31)

The durvalumab study (NCT02273375) is a phase III, prospective, double-blind, placebo-controlled, randomized study of patients with completely resected NSCLC. The study aims to compare durvalumab to chemotherapy after surgery. The primary outcome measure is DFS, and all patients must have NSCLC with positive PD-L1 expression. This study is sponsored by the Canadian Cancer Trials Group, and BR.31 is an international intergroup trial that involves the Chinese Thoracic Oncology Group. This trial is currently recruiting patients in China, and the estimated study completion date is January 2025.
Clinical trials for only Chinese patients
Pembrolizumab (KEYNOTE 032) and durvalumab (NCT02978482)

There are no available clinical data regarding pembrolizumab and durvalumab among Chinese patients. The phase I trials were launched in August 2016 and December 2016 and aim to assess the safety, tolerability, pharmacokinetics, and efficacy of these agents among Chinese patients. The KEYNOTE 032 study focuses on pembrolizumab monotherapy for patients with locally advanced or metastatic NSCLC. The durvalumab study evaluates the combination of durvalumab plus tremelimumab for patients with advanced malignancies. KEYNOTE 032 has not started recruiting patients in China. The durvalumab trial (NCT02978482) is currently recruiting patients in China, and the estimated study completion date is June 28, 2018.
Domestic clinical trials
Significant efforts by the Chinese government during the last 2 years have led to improvements in the overall clinical research environment [14]. Now the CFDA is actively reforming the regulatory framework for the approval of novel agents, which has introduced a “four-color light” strategy and will likely further adjust its policies to reflect advances in large international clinical trials of immunotherapy [15]. Chinese pharmaceutical companies had developed eight anti-PD-1/PD-L1 inhibitors by January 7, 2017, and four drugs (JS001, SHR-1210, IBI308, and BGB-A317) have been approved by the CFDA for phase I trials among patients with advanced solid tumors and NSCLC. Another four drugs (Jirnuo monoclonal antibodies, GLS-010, KN035, and WBP3155) are now being considered by the CFDA for clinical trial approval (Fig. 2). In November 2016, the PD-1 inhibitor KN035, ​that is administered by subcutaneous injection, received approval from the American Food and Drug Administration for clinical trial conduction.
Fig. 2

The development process of eight national anti-PD1 and PD-L1 inhibitors. The agents on the left were approved by the Chinese Food and Drug Administration for clinical trials, and the agents on the right have applied for clinical trial approval. Blue rectangles indicate PD-1 inhibitors, and orange rectangles indicate PD-L1 inhibitors
SHR-1210 (CTR20160175 and CTR20170090)

SHR1210 is an anti-PD-1 checkpoint inhibitor that was developed by Shanghai Hengrui Pharmaceutical Co. Ltd. The CTR20160175 trial is estimated to enroll 32–51 Chinese patients with advanced solid tumors (e.g., lung cancer, nasopharyngeal carcinoma, esophagus carcinoma, gastric carcinoma, and hepatic carcinoma). The main purpose of this study is to evaluate the drug’s safety and tolerability, which would lay the foundation for research regarding the drug’s delivery mode. The CTR20170090 trial is investigating a combination of SHR-1210 and apatinib, which is a first-generation oral anti-angiogenesis drug. The main objective of the phase II study is to evaluate the safety and tolerability of this combination, and a phase III trial is planned. Both trials are currently recruiting patients in China and enrolled their first patients on April 6, 2016, and March 21, 2017, respectively.
SHR-1210 (CTR20170299 and CTR20170322)

The CTR20170090 trial is a phase II, open-label, single-arm, multicenter study of patients with stage IIIB/IV NSCLC who have failed platinum-based chemotherapy. The study aims to investigate the objective response rate for SHR-1210 among patients with varying PD-L1 expressions (proportion score of ≥50%). Patients with EGFR mutations or ALK fusions may have received tyrosine kinase inhibitor treatment. The CTR20170322 trial is a phase III, open-label, randomized multicenter study that compares SHR-1210 plus pemetrexed and carboplatin versus pemetrexed plus carboplatin for patients with stage IIIB/IV non-squamous NSCLC. Patients have wild-type EGFR and ALK, and PD-L1 expression is not considered. The primary endpoint is PFS. Both trials have not started recruiting patients in China.
JS-001 (CTR20160274)

JS-001 is a recombinant humanized monoclonal antibody to PD-1 that was developed by Shanghai Junshi Biosciences Co., Ltd. This drug was the first PD-1 inhibitor to be approved for clinical trials by the CFDA. The CTR20160274 trial is a phase I, single-arm, non-randomized study that aims to evaluate the safety, tolerability, and antitumor activity of the drug among Chinese patients with advanced or recurrent malignant tumors. The expression of PD-L1 is not mentioned in the study’s protocol. This clinical trial is currently recruiting patients in China.
IBI308 (CTR20160735)

IBI308 is a powerful antibody to PD-1 that was developed by Innovent Biologics. Compared to other drugs, IBI308 has a higher affinity for PD-1 and induces PD-1 endocytosis to activate T cells. Preclinical data suggest that the drug provides good anti-tumor efficacy, and the CTR20160735 trial is a phase I study that is evaluating the safety, tolerability, and antitumor activity of IBI308 alone or in combination with chemotherapy among Chinese patients with malignant tumors (e.g., lung carcinoma, hepatic carcinoma, and melanoma). The primary outcome is the therapeutic efficacy of the two IBI308-containing regimens, based on the immune-related Response Evaluation Criteria. The study also aims to identify potential prognostic biomarkers using tumor tissues from patients who experienced a curative effect. This clinical trial is currently recruiting patients in China and enrolled its first patient on October 24, 2016.
BGB-A317 (CTR20160872)
BGB-A317 has been specifically designed to block the binding activity of the Fc-gamma receptor I. At the 2016 meeting of the American Society of Clinical Oncology, BeiGene reported preliminary clinical data from an Australian phase I study of patients with 26 different types of tumors (although the tumors did not include lung cancer or melanoma). The CTR20160872 trial is a phase I study that aims to assess the safety, tolerability, pharmacokinetics, and antitumor activity of BGB-A317 among Chinese patients with advanced solid tumors, such as lung carcinoma, hepatic carcinoma, and gastric carcinoma. A phase III study will be launched in 2017 and will incorporate PD-L1 testing using immunohistochemistry. This clinical trial has started recruiting patients in China (Table 2).
Table 2

Ongoing clinical trials with domestic PD-1 or PD-L1 inhibitors on advanced tumors and NSCLC

Drugs and indentifier


The role of China


Phase


Indication


Design


State


Enrollment

SHR-1210

CTR20160175


Sponsor


I


Advanced solid tumors


Non-randomized, open-label, single-center, dose-escalation


Recruiting


45

SHR-1210

CTR20170090


Sponsor


II S + A


Advanced NSCLC


Non-randomized, open-label, single-center, dose-escalation


Recruiting


118

SHR-1210

CTR20170299


Sponsor


II


Advanced NSCLC


Open-label, single-arm, multicenter


Not yet recruiting


120

SHR-1210

CTR20170322


Sponsor


III S + P + C


Advanced non-squamous NSCLC


Randomized, open-label, multicenter


Not yet recruiting


412

JS-001

CTR20160274


Sponsor


I


Advanced solid tumors


Open-label, single-group assignment


Recruiting


54

IBI308

CTR20160735


Sponsor


I


Advanced malignant tumors


Non-randomized, open-label, single-group assignment


Recruiting


104

BGB-A317

CTR20160872


Sponsor


I


Advanced solid tumors


Non-randomized, open-label, single-group assignment


Not yet recruiting


300

NSCLC non-small cell lung cancer, S + A SHR-1211 plus apatinib, S + P + C SHR-1210 plus pemetrexed and carboplatin
Discussion

Immunotherapy using PD-1 or PD-L1 inhibitors provides durable clinical regression, good tolerance, and relatively few adverse events among patients with malignant tumors. However, Chinese patients have limited access to these promising immune-checkpoint inhibitors, such as antibodies to PD-1 and PD-L1. Furthermore, the ongoing international and domestic clinical trials have duplicated the designs of previous trials for PD-1 and PD-L1 antibodies, which have revealed promising results, but rarely consider the characteristics of the Chinese or Asian populations.

The characteristics of Chinese patients are important considerations in trial designs, as the Chinese population has relatively high rates of hepatitis B virus infection and traditional medicine use [16]. Thus, many Chinese patients are ineligible for clinical trials of the antibodies to PD-1 or PD-L1. Furthermore, Chinese and international researchers have revealed that Chinese patients with NSCLC may have more driver gene mutations, different gene profiles, better clinical responses to chemotherapy, and different toxicity profiles [17–20]. However, the relevance of these characteristics remains unclear for immunotherapy with blockade of the PD-1 pathway, and data from Chinese patients remain scarce.

At the 14th Lung Cancer Summit, Chinese scientists introduced several proposals for immunotherapy using PD-1 or PD-L1 inhibitors. First, the much higher proportion of EGFR mutation should be considered when designing Chinese immunotherapy trials, as the prevalence of EGFR mutations is approximately 50% among Chinese patients with NSCLC [21, 22]. Second, the introduction of four FDA-approved immunohistochemistry biomarker assays, and the development of domestic reagents, may allow for the development of PD-1 immunohistochemistry assays in China. A phase II single-arm study of SHR-1210 as a second-line NSCLC treatment is aiming to determine an optimal PD-L1 cut-off value for Chinese patients.

Global researchers remain faced with unanswered questions regarding PD-1 and PD-L1 inhibitors. First, the relationships between PD-L1 expression and other factors (e.g., mutational burden, smoking index, and neoantigen quantity) are very complicated [23, 24], and further research is needed. Second, it would be useful to develop combined biomarkers and complementary assays that could improve the overall specificity (58%) and sensitivity (72%) of PD-1 expression [1, 25]. Third, it is possible that combining immunotherapy with chemotherapy, targeted therapy, and radiotherapy could provide superior results, compared to immunotherapy alone. Fourth, although we have known that antibodies to PD-L1 have relatively low pulmonary toxicity, it remains unclear whether antibodies to PD-1 or PD-L1 provide a better clinical response. Fifth, the conventional Response Evaluation Criteria In Solid Tumors are not appropriate for evaluating PFS after immunotherapy and pseudo-progression, and additional research is needed to improve the utility of immune-related response criteria [26].
Conclusions

Chinese clinical trials using PD-1 or PD-L1 inhibitors remain in their early stages, and further efforts are needed to improve the design of future clinical trials. In addition, China must take steps to help translate the results of clinical trials into clinical practice. For example, it will be useful to simplify phase I study designs and speed up late-stage clinical development.
Abbreviations

ALK:

Anaplastic lymphoma kinase

CFDA:

Chinese Food and Drug Administration

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

DFS:

Disease-free survival

EGFR:

Epidermal growth factor receptor

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PD-1:

Programmed cell death protein-1

PD-L1:

Programmed cell death protein ligand 1

PFS:

Progression-free survival

SCLC:

Small cell lung cancer

SoC:

Standard of care

Declarations
Acknowledgements

Not applicable
Funding

This study is supported by the Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (Grant No. 2012A061400006), the Special Fund for Research in the Public Interest from National Health and Family Planning Commission of PRC (Grant No. 201402031), and the Research Fund from Guangzhou Science and Technology Bureau (Grant No. 2014Y2-00050).
Availability of data and materials

All data generated or analyzed during this study are included in this published article.
Authors’ contributions

YL designed the outline of the manuscript. SY and YL drafted the manuscript and designed and finalized the figures and tables. Both authors read and approved the final manuscript.
Ethics approval and consent to participate

Not applicable
Consent for publication

Not applicable
Competing interests

The authors declare that they have no competing interests.
Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
(1)Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences and School of Medicine of South China University of Technology
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New Immunotherapy Strategies in Breast Cancer
Lin-Yu Yu,1,2 Jie Tang,1,2 Cong-Min Zhang,1,2 Wen-Jing Zeng,1,2 Han Yan,1,2 Mu-Peng Li,1,2 and Xiao-Ping Chen1,2,*
William Chi-shing Cho, Academic Editor
Author information ► Article notes ► Copyright and License information ►
Abstract

Breast cancer is the most commonly diagnosed cancer among women. Therapeutic treatments for breast cancer generally include surgery, chemotherapy, radiotherapy, endocrinotherapy and molecular targeted therapy. With the development of molecular biology, immunology and pharmacogenomics, immunotherapy becomes a promising new field in breast cancer therapies. In this review, we discussed recent progress in breast cancer immunotherapy, including cancer vaccines, bispecific antibodies, and immune checkpoint inhibitors. Several additional immunotherapy modalities in early stages of development are also highlighted. It is believed that these new immunotherapeutic strategies will ultimately change the current status of breast cancer therapies.
Keywords: breast cancer, immunotherapy, cancer vaccines, bispecific antibodies, immune checkpoint inhibitors, stimulatory molecule agonists
1. Introduction

Breast cancer is the most commonly diagnosed cancer and major cause of cancer death among women in less developed countries, with 882,900 cases diagnosed and 324,300 deaths in 2012, accounting for 25% of cancer cases and 15% of cancer deaths among females [1]. Risk factors for breast cancer include reproductive and endocrine factors such as the use of oral contraceptives, never having children, and a long menstrual history. Potentially modifiable risk factors include drinking, obesity, physical inactivity, and use of menopausal hormone therapy [2].

Recent studies classify breast cancer into four subtypes: Luminal A (ER+/PR+/HER2−, grade 1 or grade 2), Luminal B (ER+/PR+/HER2+, or ER+/PR+/HER2− grade 3), HER2 overexpression (ER−/PR−/HER2+), and triple negative breast cancer (TNBC, ER−/PR−/HER2−). Luminal A subtype has a good prognosis and is sensitive to endocrine therapy, thus, general treatment can be endocrine therapy alone. Luminal B subtype is associated with high rate of tumor proliferation, among which HER2 negative Luminal B subtype is typically treated with endocrine therapy + chemotherapy; and HER2-positive Luminal B subtype is general treated with chemotherapy + anti-HER2 treatment + endocrine therapy. HER2 overexpression subtype features with poor prognosis and rapid progression, and the main recommended treatment is chemotherapy + anti-HER2 treatment. The negative expression of ER, PR and HER2 in TNBC has unique biological characteristics and strong heterogeneity, no standard treatment but chemotherapy is suggested for the subtype. Although recent progresses in early diagnosis and treatments have made breast cancer a treatable disease, multidrug resistance (MDR) remains the main obstacle in the treatment of metastatic breast cancer and the survival of patients with metastatic breast cancer is still 2–3 years [3,4].

Breast cancer is immunogenic, and multiple putative tumor-associated antigens (TAAs), such as HER-2 and Mucin 1 (MUC1), are observed in the cancer. These TAAs have been the successful targets of new drug development for cancer vaccine and bispecific antibody (bsAbs) over the past decade, some of which have been translated into tumor-specific immune responses and are proven to be clinically beneficial [5,6]. There is a growing body of evidence to support the fact that the immune cells in tumor microenvironment can effectively promote or inhibit tumor growth, which can be used as a prognostic indicator for breast cancer [7,8]. The immune cells in breast cancer tissue are mainly composed of T-lymphocytes (70%–80%), and the rest derived from B-lymphocytes amacrophages, natural killer cells and antigen-presenting cells (APCs) [9,10]. T-cells are activated by the recognition to tumor antigens submitted by APCs, and the strength and quality of the T-cell activation signals are connected with various receptor-ligand interactions [11] (Figure 1).
Figure 1
Figure 1
Schematic of action of selected immunotherapies in breast cancer. ① Vaccines initiate an immune response by providing target antigens to DCs and triggering their activation. Adaptive immune responses initiate at the lymph node through the interaction ...

First, the immune checkpoint signals of B7 family. CD28/Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and B7-1 (CD80)/B7-2 (CD86) bind early in T-cell activation, and CD28 expressed on the initial or resting T-cells, while CTLA-4 expressed after T-cell activation with the affinity higher than CD28, play a role in promotion and inhibition of T-cells, respectively. Programmed cell death-1 (PDCD1, PD-1) signal, a new member of B7 family, can inhibit the immune response after T-cell activation. Second, programming signals: stimulatory molecules and cytokines. There is a tremendous body of evidence detailing the importance of cytokines in T-cell differentiation and fate determination [12,13,14,15]. Stimulatory molecules, such as CD40, OX40 and 4-1BB, are important in programming the flavor and longevity of T-cells responses necessary for the T-cells unique contribution to the inflammatory environment, including their cytolytic functionality and cytokine production that support neighboring T-cells and the humoral response [16]. Meanwhile, immune cells which are not present within the core also play specific roles in tumor process. Macrophages comprise a larger proportion of the stroma and influence reorganization of the extracellular matrix. There are three stages during the interaction of tumor cells and immune microenvironment: removal, balance, and escape [17]. The ultimate fate of the tumor cells includes either complete eradication or evolution of tumor cell variants that escape the immune surveillance and establish measurable tumors. These variants include loss of the expression of major histocompatibility complex (MHC) class I protein, inhibition in antigen processing and presentation pathways, mutation or loss of tumor antigens, deficiency in T-cell receptor (TCR) signaling and costimulation, and deficiency in cytokines synthesis [5].

In this review we discuss new findings in breast cancer immunotherapy, including recent achievements in immune checkpoint blockades and bispecific antibodies (bsAbs). We have also discussed therapeutic cancer vaccines and highlighted several additional immunotherapeutic modalities in early stages of development. In addition to these promising early results, information on 30 ongoing clinical trials that evaluate this class of immunotherapy in breast cancer are also summarized (Table 1).
Table 1
Table 1
Examples of ongoing clinical trial of immunotherapy in breast cancer.
2. Cancer Vaccines

Cancer vaccine belong to a class of biological response modifiers and generally contains an agent that resembles a TAA or a specific marker protein of tumor-causing microorganism. The agent stimulates the body’s immune system to recognize and fight against exactly tumor cells [18]. Adjuvant, an immunological or pharmacological agent that modifies the effect of other agents, is commonly used to boost immune response, particularly for cancer patients whose immune response to a simple vaccine may have weakened. It is an active field of research about the cancer vaccine. William Coley described the successful treatment of round-cell sarcoma with the intratumoral vaccination of Streptococcus and Serratia bacterial products since the in 1910s [19]. However, a successful vaccine should be able to stimulate the immune system as well as direct it towards a viable tumor target, or target a tumor antigen which plays a key role in the process of tumorigenesis and metastasis.
2.1. Antigen-Specific Vaccines

HER2 and MUC1 are two well-studied antigens in breast cancer. 25%–30% breast cancer patients exhibit HER2 overexpression and almost all breast cancers show MUC1 expression. The design of antigen specific vaccines can enlarge adaptive immune to a therapeutically beneficial level, for the levels of HER2 or MUC1 specific T-cells and antibodies are very low in most breast cancer patients [20,21].
2.1.1. HER2-Derived Vaccines

Progresses have been made in the HER2-derived vaccines administered in the adjuvant settings. A dose schedule optimization phase I/II trial of the HER2-derived MHC class I peptide E75 with granulocyte-macrophage colony stimulating factor (GM-CSF) enrolled 195 HER2-positive breast cancer patients. The trial reported an improved 5-year disease-free survival (DFS) (89.7%) compared to GM-CSF-treated control groups (80.2%), while the local and systemic toxicities were mild [22]. AE37 is a HER2-derived MHC class II epitope targeting CD4+ T-lymphocytes which can elicit both CTL and CD4+ TH-cell responses. Result from a phase II trial that combined the AE37 peptide with GM-CSF for the adjuvant treatment of early stage breast cancers has shown similar toxicity profiles between vaccine group (AE37 + GM-CSF) and adjuvant group (GM-CSF), but a 40% reduction in recurrence was observed only in the vaccine-treated group at a median follow-up of 17 months [23].

Besides benefit from adjuvant therapy, the vaccines combined with HER2 monoclonal antibody or kinase inhibitor also obtained better curative effects. The University of Washington Tumor Vaccine Group found that combined therapy with trastuzumab (HER2 inhibitory antibody) and a HER2 vaccine boosted to greater levels of HER2-specific immune responses in patients with HER2 positive metastatic breast cancer than treated with trastuzumab alone, and the combination therapy was well tolerated [24]. It was well tolerated when HER2 vaccine was used in combination with lapatinib (tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways) in trastuzumab-refractory breast cancers with HER2-overexpression, and anti-HER2-specific antibodies and HER2-specific T-cells were induced in 100% and 8% of patients respectively. However, there was no objective clinical responses [25]. These investigations suggest that the HER2-derived vaccines possess a promising prospect of research in breast cancer treatment, especially when combined with adjuvant or HER2 monoclonal antibody and kinase inhibitor, for the mild toxicity and well clinical responses.
2.1.2. MUC1-Derived Vaccines

Mucin 1 (MUC1) is a member of the mucoprotein family and abnormally expressed in various epithelial cells and malignant tumors. MUC1 is overexpressed and aberrantly glycosylated in tumor cells, which contribute to the formation of epithelial cell carcinoma including breast cancer by promoting cell adhesion, blocking the apoptosis pathway and regulating intracellular growth signals [26]. MUC1 is the target of breast cancer early diagnosis biomarkers CA27-29 and CA15-3. Theratope (STn-KLH) is a therapeutic cancer vaccine that consists of a synthetic antigen including MUC1. In a phase III study involving 1208 patients with metastatic breast cancer treated with theratope concomitant endocrine, significantly longer time to progression (TTP) and overall survival (OS) than control group was observed, and this advantage is particularly pronounced in patients who have a robust antibody response to theratope. [27]. For the 12 breast cancer patients who were given monthly PANVAC vaccinations, a poxviral vaccine containing transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules, the side effects were some mild injection-site reactions, and 33% patients showed stable disease (SD) and 8% had a complete response (CR). Patients who had limited tumor burden, better CD4 response or higher number of CEA specific T-cells appeared to benefit from the vaccine [28].

L-BLP25 is a MUC1 antigen-specific vaccine. L-BLP25 vaccine in combination with letrozole could induce an antigen-specific immune response and increase the survival advantage obviously in MUC1-expressing breast cancer mouse model [29]. The PEGylated gold nanoparticle (AuNP)-based vaccine immobilizes chimeric peptides which consists of a glycopeptide sequence derived from MUC1 and the T-cell epitope P30 sequence, and this vaccine is able to significantly induce mice MHC-II mediated immune responses. Meanwhile, the antisera from AuNP treated mice can recognize human MCF-7 breast cancer cells [30]. Based upon these data, future trials evaluating the therapeutic effects of MUC1-derived vaccine in breast cancer are anticipated.
2.2. Cell-Based Vaccines

As vaccine responses are driven by APC, an effective approach to obtain the most effective APC is synthesis of dendritic cells (DCs) loaded with tumor antigen ex vivo and then administered to patients for immunotherapy. These vaccines present tumor antigens and activate tumor immunity directly or indirectly counting on the power of DCs [31].

Lapuleucel-T (APC8024) was prepared from peripheral-blood mononuclear cells (PBMC) and consisted of the sequences of HER-2 linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). Lapuleucel-T was well tolerated in the clinical trial involving 18 lapuleucel-T treated patients with metastatic HER2+ breast cancer, without grade 3 or 4 adverse events. In addition, there was significant HER2-specific T-cell proliferation and 5.5% partial response (PR), 16.6% experienced SD lasting >1 years [32]. P53 serves as a favorable immunologic target as mutations are found in up to 30% of breast cancers. Spontaneous p53-reactive T-cells have been identified in more than 40% of patients with breast cancer-treated; In addition, the majority of breast cancer patients with high p53 expression have the ability to initiate p53-specific IFN-γ response [33]. In a phase II trial of a P53 DC vaccine involving 26 subjects with verified progressive breast cancer, among 19 patients continue treatment after 6 vaccinations weeks, 42% attained SD, indicating an efficacy of p53-specific immune therapy. The efficacy was associated with tumor p53 expression, p53 specific T-cells and serum YKL-40 and IL-6 levels [34]. Another clinical trial with P53 DC vaccine in combination with indoximod (IDO inhibitor) showed no effect, but it seems to benefit the subsequent salvage chemotherapy, and the causality is still in research (ASCO 2013 abstract 3069).
3. Bispecific Antibodies

Bispecific antibodies (bsAbs) contain specificities of two antibodies within a single molecule and address different antigens or epitopes simultaneously. At present, the majority of bsAbs for cancer immunotherapy were engineered to redirect immune effector cells to assemble and kill tumor cells. These bsAbs consist of one arm that binds a TAA on malignant cells and another arm that binds an activator receptor on immune effector cells, hence simultaneously togethering effector cells to the tumor and triggering their cytolytic activity for tumor killing [35].

Catumaxomab, a trifunctional antibody (triomab), is the first bsAb received market approval in 2009, and is used in the treatment of malignant ascites. It targets the EpCAM on tumor cells, and recruits T effector cells via binding to the CD3 subunit of the T-cell receptor complex, and could also activate monocytes, macrophages, dendritic cells, and NK cells at the same time by binding Fcγ-receptor [36]. In December of 2014, the second bsAb blinatumomab was approved for the therapy of patients with B cell acute lymphoblastic leukemia (BcellALL). Blinatumomab acts by binding CD3 and the CD19 antigen on ALL cells and features small size and lack of Fc region (BiTE) [37].

In light of these treatment application, bsAbs used for breast cancer immunotherapy are underway, even though almost in the stage of design or preclinical studies [38]. Ertumaxomab is an intact triomab targeting CD3 and HER2 simultaneously. The safety and antitumor efficacy was confirmed in preclinical studies and a phase I clinical trial in HER2 positive metastatic breast cancer patients. Most drug-related adverse events were mild, transient and reversible. The objective response rate (ORR) was 33% in 15 evaluable patients [6]. The ability of ertumaxomab to induce cytotoxicity against tumor cell lines with low HER2 antigen density, may provide a novel therapeutic option for breast cancer patients when trastuzumab treatment is inappropriate [39]. Recently, BsAb that armed activated T-cells (ATC) and expanded from leukapheresis product by IL2 and anti-CD3 monoclonal antibody, became a popular immune treatment model for research. In a phase I immunotherapy trial involving 23 women with metastatic breast cancer (MBC) treated with anti-CD3/anti-HER2 BsAb armed ATC along with low-dose IL-2 and GM-CSF, no dose-limiting toxicities was observed, 59.1% evaluable patients had SD or better. The median OS is 40 and 57.9 months for the HER2 0–2+ and HER2 3+ patients with SD, which were both improved since the median OS data prior to therapy are 27.4 and 57.4 months, respectively. At the same time, this treatment can induce both PBMC specific anti-SK-BR-3 and innate immune responses in women with MBC with a possible survival benefit [40]. However, further clinical trials are needed.
4. Immune Checkpoint Therapy

The genetic changes along with carcinogenesis provides a lot of immunogenic targets that can be recognized by the immune system [41]. Nevertheless, the functions of adaptive immune system are always inhibited by pathways that are dysregulated in tumors [42]. Immune checkpoints are cell surface molecules that play important physiologic roles in modulating immune response, preventing autoimmunity, and maintaining self-tolerance [43,44]. These surface receptors or ligands mediate immune inhibition in tumor microenvironment can result in suppression of the activation signal of original T-cells and infiltrating T-cells. Inhibitory antibodies targeting immune checkpoints have shown a great potential for the treatment of several solid cancers such as melanoma, bladder cancer, non–small cell lung cancer (NSCLC), and breast cancer [45,46,47,48]. Currently, immune checkpoint therapies by targeting CTLA-4, PD-1, or lymphocyte activation gene-3 (LAG-3) pathways for breast cancer are still in clinical trial.
4.1. CTLA-4 Inhibitors

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is the first immune checkpoint molecule shown to enhance antitumor immunity when inhibited [49]. It is known that two signal ways are required for T-cell activation: the first signal is the antigen recognition by TCR, and the second signal comes from the stimulus molecular combination of B7 and CD28. CTLA-4 is a CD28 homologue that binds to B7 with a higher affinity to out-compete the CD28 function and prevents T-cell from receiving a second signal [50]. CTLA-4 is upregulated after T-cell activation, providing a new insight into interfering with the inhibition of T-cell activation and antitumor therapy.

CTLA-4 inhibitors caused a series of immune-related adverse reaction (irAEs) due to enhanced T-cell activation, which included hypophysitis, thyroiditis, colitis, and hepatitis. In addition, a considerable rate of irAEs was related to a significant rate of objective responses (OR) [11,51]. The mechanism may partially be explained by the reason that CTLA-4 is highly expressed on regulatory T-cells, which plays an important role in maintaining peripheral tolerance [52].

In addition to being FDA approved for melanoma, there are emerging trials regarding CTLA-4 inhibitors for breast cancer. Twenty-six patients with advanced, hormone-responsive breast cancer were given tremelimumab plus exemestane in a phase I clinical research [53]. This combination therapy was tolerable with the most common adverse reactions being diarrhea (46%) and pruritus (42%), and none developed grade 3 or 4 treatment-related diarrheas among 13 patients treated at the maximum tolerated dose (MTD). The trial reported a 42% SD lasting ≥12 weeks in patients utilizing this combination therapy, which was not worse than exemestane alone. The results showed no association between treatment efficacy and total counts or percentage of CD4/CD8 T-cells, but was associated with increased ICOS+ T-cells, which likely signals immune activation secondary to CTLA-4 inhibitor. Two other clinical trials about CTLA-4 inhibitor are ongoing: tremelimumab in combination with anti-B7H1 monoclonal antibody MEDI4736 in treatment of HER2 negative breast cancer (NCT02536794; Table 1) and ipilimumab in combination with anti-B7H3 monoclonal antibody MGA271 in treatment of TNBC (NCT02381314; Table 1). After all, further investigations are required to determine the CTLA-4 inhibitor safety profile and whether the outcome would be synergistic when used in combination with other agents or may accompanied by chemotherapy or radiation.
4.2. PD-1/PD-L1 Inhibitors

The programmed cell death-1 (PDCD1, PD-1) is expressed and remains upregulated during initial T-cell activation. The major ligand partners for PD-1 are PD-L1 (CD274 or B7-H1) and PD-L2 (CD273 or B7-DC). The PD-1 signal pathway has emerged as an interesting cancer therapeutic target [38]. Different from CTLA-4 that inhibits immune response at the initial T-cells activation step, PD-1 downregulates ongoing immunological effect at sites of reaction, that is, either in the periphery or in the neoplasm tissues [11]. PD1 is widely expressed on several immune cells including CD4+ and CD8+ T-cells, B cells, NK cells and T regulatory cells, and PD-L1 is a potential response marker for PD1/PD-L1 targeted therapies in major studies.

PD-L1 protein expression is detected in 20%–30% breast cancer patients, especially in TNBC [54], while PD-L1 mRNA expression is detected in substantially larger subsets of breast tumors [55,56]. The clinical benefit of PD-1/PD-L1 inhibitor is associated with the expression level of PD-L1, though there is also study demonstrated clinical outcomes in PD-L1 negative tumors [57]. By contrast, PD-1/PD-L1 inhibitors showed lower incidence of irAEs, most grade 1 or 2. The most possible explanation may be that the PD-L1 expression is mostly limited to tumor and location of active inflammation which functions to down-modulate an immune response during the effector phase [58].

Nivolumab is the first anti-PD-1 antibody in clinical trials and shows a 31% objective response and median OS of 16.8 months in melanoma [59]. It is now approved for use in metastatic NSCLC and advanced melanoma. The existing studies in animal models [60,61,62] and clinic trials have shown that the PD-1/PD-L1 inhibitors also have potency for the treatment of breast cancer. In a non-randomized phase I study that enrolled 32 patients with PD-L1 positive recurrent/metastatic TNBC, the preliminary results showed that single agent pembrolizumab treatment is tolerated with 15.6% experienced at least one drug-related serious adverse event, and 16.1% of patients had a PR, 9.7% had SD [63], which was similar to the finding in PD-L1+/ER+/HER2− metastatic breast cancer [64]. Two new PD-L1 inhibitors, atezolizumab and avelumab, are also under clinical trial. The efficacy of atezolizumab activity was assessed in 21 PD-L1-positive TNBC, with 24% objective responses (ORs): 10% showed complete response (CR) and 14% showed PR; 29% patients had progression-free survival of 24 weeks or longer. Such clinical efficacy is difficult to be achieved if these patients were treated with chemotherapy. However, several adverse reactions were also observed [40]. Combination of atezolizumab and nab-paclitaxel is tolerable with promising activity in patients with Metastatic TNBC [65]. Based on these preliminary results, a further Phase III study evaluated the combination therapy of atezolizumab and nab-paclitaxel in metastatic TNBC is ongoing (NCT02425891; Table 1). Another phase I study reported the clinical activity of avelumab in a cohort of patients with locally advanced or metastatic breast cancer. Avelumab have an acceptable safety profile with the most common were fatigue (19.6%), nausea (14.3%), and infusion-related reactions (11.9%), and there were 8.8% PRs in TNBC (five of 57), and all of the PD-L1+ PRs patients (four of 12) were TNBC [66]. It is meaningful to find an effective treatment with significant therapeutic activity in the heavily recurrent/metastatic TNBC, as most of these patients had received and progressed on multiple lines of therapy for advanced disease.
4.3. LAG-3 Target Therapy

Lymphocyte activation gene-3 (LAG-3) is a receptor to MHC class II, which binds with higher affinity than CD4. The protein is expressed in the activated T-cells, NK cells and DCs. LAG-3 is reported to negatively regulate the activation, proliferation, and homeostasis of T-cells, in a similar fashion to CTLA-4 and PD-1, and also plays a role in Tregs suppressive function [67]. LAGs are known to be involved in the maturation and activation of DCs. IMP321 is a soluble form of LAG-3 that functions as an APC active agent. A Phase I/II study has evaluated the effect of combined therapy with paclitaxel plus IMP321: patients with metastatic breast carcinoma were administered IMP321 every 2 weeks subcutaneously with weekly 80 mg/m2 intravenous paclitaxel. The combined therapy induced both a sustained increase in the number of activated APC and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T-cells. The trail reported 50% ORR and 90% clinical benefit in 6 months in patients utilizing combined therapy compared to 25% ORR and <50% clinical benefit in the historical control group. No clinically significant IMP321-related adverse events were reported [68]. A phase II trial with combination of IMP321, placebo, and paclitaxel is ongoing (NCT02614833; Table 1).
5. Stimulatory Molecule Agonist Antibodies

Besides immune checkpoints providing a negative signal to T-cells activation, a number of positive molecules, whose engagement upregulates T-cell function. The eventual outcome of T-cell activating interaction involves an integration of both the negative and positive signals present during that interaction. Though it is still in early stages of research, stimulatory molecule agonist antibodies have enormous potential in breast cancer and are introduced here with an eye on future development.
5.1. OX40 Agonist Antibodies

OX40 (CD134) is a member of the TNF receptor superfamily, a stimulatory molecule that are expressed in activated immune cells and tumor infiltrating lymphocytes (TILs) in breast cancer, and the expression can be increased gradually as soon as T-cells identify their specific antigens [69]. The engagement between OX40 on a T-cell and OX40 ligand on an APC not only provides a powerful stimulatory signal to the T-cells, but also provides an inhibitory signal to Tregs [70]. Based on preclinical cancer models that showed potent antitumor activity against multiple tumor types of anti-OX40 antibody, which is dependent on both CD4+ and CD8+ T-cells [71,72,73,74], a phase I study showed that OX40 agonist antibody (9B12) induced the regression of at least one metastatic lesion in 40% (12/30) patients with advanced cancer with acceptable toxicity (most toxicity was grade 1 or 2). Addition to clinical effects, the immunologic effects were increased including proliferation of circulation CD4+ and CD8+ T-cells, responses to recall and naive reporter antigens, and endogenous tumor-specific immune responses [75]. A second anti-OX40 antibody (MEDI6469) is now undergoing phase I/II clinical trials in combination with stereotactic radiotherapy in progressive metastatic breast cancer (NCT01862900). Base on immunologic effects of anti-OX40, it is rationale for application in conjunction with other therapy agent, such as vaccination, to increase T- and B-cell responses to immunize antigens in future clinical studies.
5.2. 4-1BB Agonist Antibodies

4-1BB is also a member of the TNF receptor superfamily which can be induced on diverse immune cell populations following activation, such as T-cells, NK cells, regulatory T-cells, and NK T-cells (NKT) [76]. The engagement of 4-1BB and 4-1BBL, which are predominantly expressed by activated APCs can induce an activating signal in CD8+ T-cells and NK cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic activity, and antibody-dependent cell-mediated cytotoxicity (ADCC) [77,78]. Urelumab (BMS-663513) is a monoclonal antibody specific for 4-1BB during phase II testing in melanoma [79]. As 4-1BB agonistic antibody stimulates the activation of NK cells which may enhance NK cytotoxic function, there is an alternative approach aiming at enhancing ADCC by stimulation of NK cells with an anti-4-1BB agonistic antibody. Results have shown that antibodies targeting 4-1BB synergized with trastuzumab can kill tumor cells more efficiently in murine xenotransplant models of human breast cancer [80]. 4-1BB serves as a potential vaccine target in breast cancer, but has yet to be evaluated in humans.
5.3. CD40 Agonist Antibodies

CD40 is also a member of the TNF receptor superfamily and a stimulatory protein found on APCs and is required for their activation. The CD40 ligation plays a role in APCs stimulation and maturation leading to an increase in antigen presentation and cytokine production, and a subsequent increase in the activation of antigen specific T-cells [81]. The first CD40 agonist monoclonal antibody observed in patients with solid tumors is CP-870,893. In a phase I study in patients with stage III and IV solid malignancies, CP-870,893 was well tolerated, and 27% of melanoma patients had a partial response [82]. Kawaguchi et al. suggested that mRNA expressions of CD40 in PBMCs are affected by breast cancer disease progression [83]. CD40 stimulation by its soluble recombinant human CD40 ligand directly inhibits human breast cancer cells in vitro and in SCID mice model [84]. A clinical study reported a significant difference in expression of cytoplasmic CD40 between breast cancer subtypes, and cytoplasmic expression of CD40 is related to a better prognosis [85], which suggest that CD40 may have potential as a new prognostic factor in breast cancer.
6. Conclusions

Breast cancer can be immunogenic, and the tumor immune microenvironment induced several local immune responses in the tumor tissue. In addition to immune environment, the tumor itself, such as the type of breast tumor, the area within the tumor and microenvironment also influences tumor process. For example, each subtype of breast cancer has a distinct prognosis and natural history. Poor chemotherapy prognostic factors including lack of ER and PR expression, high tumor grade, and lymph node involvement, are associated with a significantly higher CD3+, CD8+ and FoxP3+ cellular infiltrate. The immunotherapy effect can be influenced by immune cells intratumoral and peritumoral distribution, immune cells composition, and the breast tumor overall immune context and histology. The ultimate responses either suppress tumor growth or completely eliminate tumors through immune-mediated cell death, or promote tumor progression by providing inflammatory environment for tumor cells survive immunosurveillance. Nevertheless, Clinical benefits from immunotherapy for breast cancer have been shown in a growing number of trials (Table 2).
Table 2
Table 2
Examples of completed clinical trials of immunotherapy in breast cancer.

Current immunotherapy is still in its infancy for breast cancer. As mentioned above, it cannot be denied that a portion of breast cancer patients can’t benefit from these immunotherapy strategies. Despite the clinical benefit of PD-1/PD-L1 inhibitor is affected by the expression level of PD-L1, the majority of patients (76%) with PD-L1-positive TNBC were completely refractory to atezolizumab therapy [45], which indicated interindividual difference in drug response. As a heterogeneous disease, breast cancer is characterized by diversified molecular phenotypes that correlate with different drug resistant and treatment outcomes. For example, genetic polymorphisms of CYP1B1 and ABCB1 are associated with the clinical response to chemotherapy in breast cancer [86]. Since breast cancer is also an immunogenic disease, part of the patients does benefit from immunotherapy, yet it historically has been resistant to immunotherapy. With the development of molecular biology and genomics, pharmacogenomics has been shown to be effective in a significant proportion of cancer therapies in predicting therapeutic responses. The polymorphism number and site in Ribonucleotide reductase (RNR) showed significant correlation with leukopenia in heavily metastatic breast cancer patients with gemcitabine monotherapy [87]. Breast cancer patients with low COX-2 expression and PIK3CA wild type tumors had worse DFS compared to all other subgroups in celecoxib treatment, which suggest COX-2 expression and PIK3CA mutation may be good prognostic and predictive biomarkers for celecoxib therapy [88]. CD95 and MBL2, two immune function genes, the promoter single nucleotide polymorphisms (SNPs) of CD95 (rs2234767) and MBL2 (rs7096206) are associated with grade 3 infection following treatment of breast cancer with cytotoxic therapy [89]. Polymorphisms in immune function genes may provide means for predicting clinical benefit or toxicity from immunotherapy. Further pharmacogenomics studies focused on immune system should be performed to elucidate the mechanisms and identify biomarker signatures in patients with higher toxicity and with resistant or responsive outcome, before the administration of immunotherapy strategies. Accordingly, pharmacogenomics may greatly improve the efficacy of immunotherapy for breast cancer as well as other cancer, and reduce the incidence of adverse reactions. Our current study revealed difference in the cytotoxicity to HER2 positive breast cancer cells when trastuzumab was incubated with PBMCs from different healthy individuals, and several polymorphisms in immune function genes have been found related to this difference (data not shown). Based on pharmacogenomics studies, these immunotherapy strategies may achieve a great success in personalized therapy and ultimately improve the current status of therapy for breast cancer patients.
Acknowledgments

This project was supported by National Science and Technology Major Project (2013ZX09509107), National Natural Science Foundation of China (No. 81422052, No. 81373489, No. 81170091), Hunan Provincial Natural Science Foundation of China (13JJ1010).
Author Contributions

Lin-Yu Yu conceived the review, generated the first draft, and overall, led the writing of the manuscript and the manuscript was supervised and finalized by Xiao-Ping Chen. All the authors read, edited and approved the final version of the manuscript.
Conflicts of Interest

The authors declare no conflict of interest.
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Re: Chinese pharmaceutical patent cancer drug precisely target cancer cell sold $bill



http://news.sina.com.cn/o/2017-09-04/doc-ifykpuui0877340.shtml


中科院抗癌药能精准杀肿瘤细胞 卖出4.57亿美元
2017年09月04日14:28 澎湃新闻
中科院抗癌药能精准杀肿瘤细胞 卖出4.57亿美元



　　原标题：中科院抗癌新药能精准杀死肿瘤细胞，卖出4.57亿美元

　　人民日报客户端9月4日报道，一个正在开发中的新药苗子能卖30亿人民币？这不是天方夜谭。今天中国科学院上海有机化学研究所与信达生物制药（苏州）有限公司达成授权开发达成合作协议：信达生物以首付款、研发里程碑和销售里程碑付款共计4.57亿美元另加销售提成的方式，获得中科院上海有机所研发的肿瘤免疫靶向小分子抑制剂IDO的全球独家开发许可权。

　　这是迄今为止我国制药领域金额最大的院企合作项目，堪称中国院企合作创新开发新药的重要里程碑。

　　据中科院上海有机所相关负责人介绍，创新药研发是当前国际科技竞争的重要战略制高点，其中，肿瘤免疫治疗药物的研发备受各国关注。近年来国内外临床研究证明，PD-1抗体是目前最有效的肿瘤免疫治疗药物，PD-1抗体与IDO抑制剂的联合疗法已取得令人满意的临床结果。

　　信达生物由“千人计划”国家特聘专家俞德超博士创办，于2011年在苏州生物医药产业园成立。该公司致力于开发、生产抗体新药，PD-1抗体是该公司的拳头产品，目前已进入三期临床。2015年，信达生物与世界制药巨头美国礼来两次就PD-1抗体等研发项目达成战略合作，信达生物共获得33亿美元的潜在合作金额，此项合作使当时成立仅三年多的信达生物在国际生物制药领域受到高度关注。

　　“中科院上海有机所研发的IDO抑制剂与我们当前正在开发的PD-1抗体有着潜在的协同治疗效果。”俞德超介绍，“此次合作，是中国创新资源在肿瘤免疫疗法上的‘强强联合’，不仅能推动合作成果早日惠及中国乃至全球病人，还将推动中国生物药抢占国际市场，在国际生物制药领域打响‘中国创新’品牌。”

　　此次双方达成合作的IDO小分子抑制剂全名为“吲哚胺2，3-双加氧酶”，由中国科学院上海有机化学研究所王召印、朱继东研究员研发获得。目前科学试验已证实，在前列腺癌、胰腺癌、乳腺癌、胃癌等多种肿瘤细胞内都有IDO 的过度表达。所谓IDO的过度表达，是指肿瘤细胞通过过度释放IDO阻止免疫细胞增殖激活，从而使肿瘤细胞逃避免疫系统的监视、“逍遥法外”，这也是早期癌症难以被免疫系统发现的原因之一。IDO抑制剂可以对IDO的过度表达进行抑制，从而使免疫细胞恢复活性，精准杀死肿瘤细胞，使PD-1抗体在治疗肿瘤中产生“如虎添翼”的效果。


责任编辑：桂强
文章关键词： 中科院 信达 肿瘤

Re: Chinese pharmaceutical patent cancer drug precisely target cancer cell sold $bill

Cancer Loong hurry go beg 1B1R PRC for cancer drugs.