https://orcid.org/0000-0001-8263-6288
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ABSTRACT
Introduction
Immune checkpoint inhibitors have achieved great success in the treatment of many different types of cancer. Programmed cell death protein ligand 1 (PD-L1, CD274) is a major immunosuppressive immune checkpoint and a target for several already approved monoclonal antibodies. Despite this, novel strategies are under development, as the overall response remains low.
Areas covered
In this review, an overview of the current biomarkers for response to PD-L1 inhibitor treatment is given, followed by a discussion of potential novel biomarkers, including tumor mutational burden and circulating tumor DNA. Combinatorial immunotherapy is a potential novel strategy to increase the response to PD-L1 inhibitor treatment and currently, several interesting bispecific antibodies as well as bispecific fusion proteins are undergoing early clinical investigation. We focus on substances targeting PD-L1 and a secondary target, and a secondary immunomodulatory target like CTLA-4, TIGIT, or CD47.
Expert opinion
Overall, the presented studies show anti-tumor activity of these combinatorial immunotherapeutic approaches. However, still relatively low response rates suggest a need for better biomarkers.
Article highlights
Immune checkpoint inhibitors are well established in daily practice with FDA-approved antibodies against the key target programmed cell death protein ligand 1 (PD-L1, CD274).
There is still a need and challenge for biomarker development from immunohistochemical assessment and tumor mutational burden of the tumor specimen to circulating tumor DNA for accurate prediction of PD-L1 inhibitor treatment now and in the future.
As the overall response rate with checkpoint inhibitor monotherapy remains low, combinatorial immunotherapy with bispecific antibodies as well as bispecific fusion proteins is a potential new strategy to increase the response rate.
Early clinical trials using secondary immunomodulatory targets such as CTLA-4, TIGIT, or CD47 are showing encouraging and promising results, with some achieving very high disease control rates.
Abbreviations
| BC | = | breast cancer |
| CAR | = | chimeric antigen receptor |
| CCC | = | cholangiocellular carcinoma |
| CPS | = | combined positive score |
| ctDNA | = | circulating tumor DNA |
| CTLA-4 | = | cytotoxic T-lymphocyte-associated Protein 4 |
| DCR | = | disease control rate |
| HCC | = | hepatocellular carcinoma |
| IL-2 | = | interleukin-2 |
| IFN-γ | = | interferon gamma |
| LAG | = | lymphocyte-activation gene 3 |
| MSI | = | microsatellite instability |
| NK cell | = | natural killer cell |
| NSCLC | = | non-small cell lung cancer |
| ORR | = | objective response rate |
| PD-L1 | = | programmed cell death protein ligand 1 |
| PD-1 | = | programmed cell death protein 1 |
| SCLC | = | small cell lung cancer |
| TMB | = | tumor mutational burden |
| TIGIT | = | T-cell immunoreceptor with Ig and ITIM domains |
| TIM-3 | = | T-cell immunoglobulin and mucin-domain containing-3 |
| TME | = | tumor microenvironment |
| TPS | = | tumor proportions core |
| UC | = | urothelial carcinoma |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosure
A reviewer on this manuscript has disclosed they are on the advisory boards of BMS, Genentech, EMD Serono, Merck, Astrazeneca, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, Primum; a consultant or scientific advisory board member of Suba Therapeutics, Syapse, Servier, Merck, Syncorp; research support from Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics; speaker fees from BIO-INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, Aveo; data safety monitoring committee honorarium from Mereo; relative employed by Myriad; writing or editor fees from Uptodate, Practice Update, Onviv. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.