Pd-1 antibody trial

Honjo's studies suggested that suppression of the PD-1 protein could be effective in cancer treatment Studies have shown that expression of PD-1 and PD-L1 was enhanced in cancer cells and was related to defective immune responses These studies suggested that two immune checkpoint molecules may be important therapeutic targets for cancer and infectious disease treatment.

This study also showed that PD-L1 antibody affected the survival of tumor cells in vivo Honjo cooperated with Ono Pharmaceutical Co. Two studies of nivolumab conducted in Phase III trials showed impressive efficacy for this antibody in advanced melanoma 26 , The results of a phase III trial showed that the overall survival rate at 1 year was significantly different between the nivolumab group In addition, nivolumab showed higher response rates and lower toxicity rates than ipilimumab and chemotherapy Following the results of these two clinical trials, the Food and Drug Administration FDA approved nivolumab for the treatment of advanced melanoma in The PD-1 protein has led to breakthroughs in cancer immunotherapies in the past decades.

Many companies have filed patents related to antibodies during these past 20 years. Table 2 shows the core patents related to FDA-approved antibodies while Table 3 shows patents related to antibodies. The C'D loop of PD-1 mainly contributes to the interaction with pembrolizumab The epitopes of these antibodies directly occupy the partial binding site of the PD-L1 protein.

Tislelizumab interacts with an IgV-like domain of PD-1 and is different from pembrolizumab and nivolumab, as shown by its unique binding epitopes, including Gln75, Thr76, Asp77, and Arg86 Although SHR was reported to have unspecific interactions with some human receptors driving angiogenesis, the optimization of complementary determining region CDR domains successfully eliminated off-target binding Meanwhile, the binding properties of SHR have not been reported.

CX is a human PD-L1 specific protease-activatable antibody prodrug. CX was designed by linking the masking peptide links to the targeted antibody These are dominated by the VH chain The paratope of KN is limited to only two complementary determining regions CDRs —one of which contributes to binding with high-affinity There have been more than 2, clinical trials of anti-PD-1 antibodies and over 1, clinical trials of anti-PD-L1 antibodies Figure 3.

Nivolumab and pembrolizumab, two anti-PD-1 antibodies, obtained approval for cancer therapy in There are currently several FDA-approved antibodies, including nivolumab trade name: Opdivo , pembrolizumab trade name: Keytruda , cemiplimab trade name: Libtayo , atezolizumab trade name: Tecentriq , durvalumab trade name: Imfinzi , and avelumab trade name: Bavencio Table 4 In addition, camrelizumab and toripalimab were approved by NMPA for marketing.

A Numbers of clinical trials of anti-PD-1 antibodies. B Numbers of clinical trials of anti-PD-L1 antibodies. Antibodies that obtained approval for cancer therapy are indicated by an asterisk. Clinical trials of most antibodies have just started, and the results require further updating. The data from clinical trials revealed that newly developed antibodies also showed a durable response. In some patients, these AEs led to treatment discontinuation and treatment interruption.

The disease control rate DCR was Based on the clinical results shown above, cemiplimab, camrelizumab, and toripalimab were approved for clinical use.

Most seriously, AEs caused by these antibodies sometimes could lead to treatment discontinuation and treatment interruption Furthermore, small molecule inhibitors targeting PD-1 and PD-L1 are emerging as their potential advantages are realized vs. Some clinical trials have shown that more than half of patients had no response to anti-PD-1 drugs, and some responders even experience tumor relapse within 2 years after treatment of anti-PD-1 drugs 26 , In addition, BMS designed a different companion assay for PD-L1 expression using its antibody and had a patent application WOA1 that described a method of detecting PD-L1 expression using the clone antibody Recent studies e.

As is shown in Table 7 , differences between six commonly used PD-L1 IHC assay were shown by detection system, staining platform, and antibody epitope. Thus, each assay potentially displayed different staining sensitivities. Different PD-L1 IHC assays and different PD-L1 tumor expression cut-off points are used in clinical trials, which raises concerns about whether the tests can be used interchangeably. The result from phase I of the Blueprint project showed that the 22C3, , and SP assays displayed comparable sensitivity and the SP assay showed significantly less sensitivity The results from phase 2 showed highly comparable sensitivity between 22C3, , and SP assays, less sensitivity with SP assay, and higher sensitivity with assay when detecting PD-L1 expression on TC The high concordance was observed between scorings by glass slide and scorings by digital image Most importantly, a recent study has investigated the cause of distinct immunohistochemical staining generated by SP assay.

The results suggested that discordances are more likely caused by differences of staining platform rather than antibody epitope This suggests that LDH could predict early response or progression in advanced melanoma patients with anti-PD-1 therapy , High pretreatment lymphocyte count LC and relative eosinophil count REC were associated with improved overall survival of melanoma patients with pembrolizumab treatment Patients with T-cells expressing SRY-Box 2 SOX-2 experienced disease regression following the treatment of nivolumab, suggesting that SOX-2 is associated with a clinical response upon immunotherapy with anti-PD-1 monoclonal antibodies Patients with a 1.

Another study evaluated the clinical efficacy of PD-1 inhibitors in patients with MMR-deficient tumors across 12 tumor types. Besides that, rs, which maps to a locus of IL2 gene and IL21 gene, was correlated with a higher response to anti-PD-1 targeting therapy TMB is an estimate of somatic mutations by accessing the data from whole exome sequencing WES or sequencing a select panel of genes.

Foundation Medicine has developed clinical testing platforms to measure TMB using hybrid capture-based next generation sequencing. A significantly higher candidate neoantigen burden was detected in patients with CB vs. The PFS in patients with a higher non-synonymous burden were higher than those with low non-synonymous burden median PFS A recent study has shown that a minority of somatic mutations in tumors could lead to neoantigens and TMB could be used to estimate tumor neoantigen load Meanwhile, these companies have applied for a series of patents related to inhibitors Table In addition, the patents showed verified inhibitory effects of these inhibitors.

All inhibitors discovered by Aurigene, including small molecule chemical compounds and peptides, showed an inhibitory effect on the PD-1 signaling pathway.

Guangzhou Maxinovel Pharmaceuticals Co. Meanwhile, Aurigene Discovery Technologies Limited has designed a series of tripeptide peptidomimetics and developed cyclopeptides and macrocyclic-peptides based on peptidomimetics — Nearly all inhibitors are still being investigated in preclinical studies.

This has shown acceptable safety of CA The phase II study of CA showed a positive response in two patients with Hodgkin's lymphoma, and the clinical benefit rate is Due to its short half-life 6—8 h vs. This preclinical result suggested that the small molecule inhibitors may offer effective anti-tumor therapy Despite the promising results reported in some clinical trials, limited drug efficacy caused by IRAEs has been observed and durable responses have been found in only a limited number of patients.

In addition, immune-related adverse events caused by anti-PD-1 drugs have been reported in several clinical trials. However, responses were also seen in patients with negative or low PD-L1 expression. The CheckMate trial among NSCLC patients with a high tumor mutational burden showed that progression-free survival was significantly longer with first line nivolumab plus ipilimumab than with chemotherapy, regardless of PD-L1 status These studies also suggested that a higher mutation or neoantigen load could potentially result in a higher likelihood of response to PD-1 or PD-L1 inhibitors.

On the other hand, small molecules are expected to reduce immune-related adverse events and promote higher efficacy. Future clinical trial results of CA would be important for developing small molecule inhibitors.

LG organized the database collection. LG and RW wrote the first draft of the manuscript. HK wrote and revised sections of the manuscript.

All authors contributed to manuscript revision, read and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors would like to thank Ms.

Ema Zivkovic who kindly reviewed the manuscript for English editing. National Center for Biotechnology Information , U. Front Immunol.

Published online Jul 7. Author information Article notes Copyright and License information Disclaimer. Hang Fai Kwok om. This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology.

Received Apr 1; Accepted Jun 9. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Introduction Programmed cell death protein 1, also referred to as cluster of differentiation CD , is a surface protein that can regulate the immune system by inhibiting T-cell activity.

Open in a separate window. Featured Clinical Focus. October 21, Sara Karlovitch. In order to participate in the study, patients must be at least 18 years of age or older at the time of screening, have a confirmed diagnosis of one of the following: Peripheral T-cell lymphoma PCTL Angioimmunoblastic T-cell lymphoma PTCL not otherwise specified Nodal PTCL with T-follicular helper Follicular T-cell lymphoma Cutaneous T-cell lymphoma CTCL Mycosis fungoides Sezary syndrome Additionally, the patient must have received at least 2 prior systemic therapies, at least 1 measurable lesion if the patient has PTCL, patients with CTCL must have assessable disease, an ECOG performance status of , a life expectancy of at least 3 months, and adequate bone marrow, renal, and hepatic functions.

News release. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Gastric and Esophagogastric Junction Adenocarcinoma. Phase 2.

Study Type :. Interventional Clinical Trial. Estimated Enrollment :. Actual Study Start Date :. Estimated Primary Completion Date :. Patients with active hepatitis B or active hepatitis C. In addition to active hepatitis B or hepatitis C infections requiring treatment, group trials can be conducted.

Inability to swallow, intestinal obstruction, or other factors that affect drug administration and absorption. Received systemic antineoplastic therapy within 28 days before treatment, including chemotherapy, immunotherapy, biotherapy cancer vaccine, cytokines, or growth factors that control cancer , etc.. Received major surgery within 28 days before treatment or radiotherapy within 90 days before treatment.

Received live vaccination except influenza attenuated vaccine within 28 days before treatment. Patients requiring long-term systemic glucocorticoid therapy or other immunosuppressive therapy.

Allowing subjects to use local, ocular, intra-articular, intranasal and inhaled glucocorticoid therapy. Patients suffering from uncontrollable comorbid diseases, including but not limited to symptomatic congestive heart failure, uncontrollable hypertension, unstable angina, active peptic ulcer or bleeding disorders.

Pregnant or lactating women. Patients with a history of interstitial lung disease or non-infectious pneumonia. Subjects who have previously had drug-induced or radioactive non-infectious pneumonia but asymptomatic are allowed to enroll.

Any life-threatening disease, physical condition or organ dysfunction according to the researchers' judgment may endanger the safety of the subject or put the clinical research at excessive risk. Any other conditinons that the investigator considers inappropriate for participation in this study. Contacts and Locations. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.