Written by Myung Soo Kim, Research Analyst, Kineticos

In the next few days, Kineticos will be releasing a new research report focused on Immune Checkpoint Inhibitors. Given that the report covers a lot of details in an assortment of areas, I felt summarizing it beforehand would be appropriate. I just earned my Ph.D. earlier this year, so I’m very familiar with lengthy reports and journal articles, and can thus appreciate the value of a short summary or abstract. So here goes…

The report starts with a bit of background on cancer immunotherapy in general: researchers have recently been attempting to boost patients’ immune response against tumors by a variety of methods that mainly focus on stimulating or augmenting the innate T-cell response. Some such strategies include the use of anticancer vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors. These methods have been enabled by recent scientific advances that have increased our knowledge of the immune system and its response to malignancies, which have resulted in the recent clinical successes of the anti-cancer vaccine Provenge and of several immune checkpoint inhibitors. The discovery and clinical successes of immune checkpoint inhibitors specifically have revolutionized cancer immunotherapy; the cancer immunotherapy market is forecasted to reach sales of >$13B in 2023, the majority of which may be attributed to immune checkpoint inhibitors.

The report then dives into immune checkpoint inhibitors: immune checkpoints are pathways used by the immune system to maintain self-tolerance, and modulate the immune response. Cancer cells are able to co-opt some of these immune checkpoint pathways to evade the immune system, especially against T cells. Antagonists of inhibitory (immune checkpoint) molecules are able to amplify the antigen-specific T cell response to fight against cancer, and are the main types of drugs being tested for use as immune checkpoint inhibitors. The two most studied immune checkpoint receptors for cancer immunotherapy are cytotoxic T-lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) or programmed cell death protein ligand 1 (PDL1).

Next, the report discusses approved and future immune checkpoint inhibitor therapies and approaches to therapy. Several checkpoint inhibitors have been approved by the FDA, and more are in clinical trials. Ipilimumab, an anti-CTLA4 mAb (monoclonal antibody), received approval from the FDA for the first-line treatment of advanced melanoma in 2011. Nivolumab and pembrolizumab, anti-PD1 mAbs, have been approved by the FDA for the treatment of metastatic melanoma and metastatic non-small cell lung cancer (NSCLC). Recently, Bristol-Myers Squibb’s Opdivo, a PD1 inhibitor which has been approved for melanoma, metastatic renal cell carcinoma, and Hodgkin’s lymphoma, failed to meet a primary endpoint for the treatment of NSCLC. It should be noted that this clinical trial did not select for a population with high PDL1 expression. Future studies may want to use PD1 or PDL1 expression as a biomarker predictive of response, and select for a population with high PDL1 or PD1 expression when treating with anti-PD1 or anti-PDL1 antibodies. Other immune checkpoint targets such as LAG3, OX40, or TIM3 are being explored in clinical trials as well.

An interesting phenomenon has been observed when treating patients with multiple immune checkpoint inhibitors: synergy. Combining anti-CTLA4 and anti-PD1 therapies has been shown to achieve synergistic effects, significantly enhancing the antitumor immune response in both animal models and clinical trials. Furthermore, combinatorial approaches utilizing immune checkpoint inhibitors with molecularly targeted cytotoxic therapies or immunostimulatory antibodies are being investigated and may provide synergistic effects as well.

Finally, the report highlights a few challenges that immune checkpoint inhibitors face. These include immune-related adverse events which typically occur with blockade of CTLA4; fortunately, they can usually be managed without adversely affecting the anticancer effects of the therapy. Another challenge is careful patient selection and finding reliable biomarkers predictive of response to treatment, as not all patients will respond to immune checkpoint inhibitors. This challenge may be resolved with the trend towards personalized medicine; as patients begin to get their genomes sequenced en masse, choosing the right patients for receiving immune checkpoint inhibitor therapy will become less difficult. The development of companion diagnostics and finding relevant biomarkers will be critical to address this challenge.

This article preview may be enough to quench the thirst of some on this subject, but the full report covers many more aspects of immune checkpoint inhibitors, and in much greater detail. For those who may be interested in other topics, we have already published a report on Gene Editing (specifically, the CRISPR/Cas9 system), and my colleagues and I are currently working a report focused on chimeric antigen receptor T cells (CAR-T cells) therapy. I’ll be sure to provide a similar synopsis once we’re closer to publishing. Thanks for reading!

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Myung Soo Kim, Ph.D., Research Analyst, is currently responsible for supporting the delivery of customized management consulting solutions to clients across the life science ecosystem. Additionally, Dr. Kim is the lead author on several Kineticos research reports.

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