Immune Checkpoint Inhibition in Advanced Cancer

Michael Postow, MD, Memorial Sloan Kettering Cancer Center, New York, New York

Fellow summary authored by Quaovi Sodji, MD, PhD

Immune checkpoint inhibitors (ICI) have changed cancer therapy in recent years. This presentation by Dr. Postow highlighted the role and mechanism of action of ICI in the management of advanced melanoma, the potential synergism with radiation therapy (RT), novel and upcoming studies to further harness the therapeutic effects of the immune system in cancer and ways for Fellows to potentially contribute to this growing field of cancer immunotherapy.

Tumor antigens may be inherently difficult for the immune system to discriminate from self-antigens. However, in certain instances, tumors express antigens that are recognized and effectively targeted by the immune system, resulting in an effective antitumor response. The effectiveness of such a response by the immune system appears to be linked to the T cell receptor (TCR) diversity, which allows the recognition of the various tumor neo-antigens.

RT, which can be immunostimulatory, enhances the aforementioned TCR diversity by acting as an in situ vaccination capable of inducing the production and release of tumor antigens in the tumor microenvironment. This mechanism has been implicated in various cases of synergism between RT and ICI in melanoma. Nevertheless, the exact mechanisms implicated in such synergism are not completely understood.

These checkpoint inhibitors including ipilimumab and nivolumab, enhance the proliferation of T cells including CD4 and CD8 T cells. The combination of these agents leads to improved response at the expense of higher toxicities. A key question that is still investigated is the exact duration of ICI therapy, as the side effects associated with these agents can impact patients’ quality of life and in some cases can be life-threatening. Given that in some studies the efficacy of ICI, measured by the progression-free survival and overall survival are similar between patients who receive the complete course of ICI and those who discontinue therapy earlier due to toxicities, it might be possible to identify a shorter duration of ICI therapy that can be effective while minimizing side effects. This hypothesis is currently being tested through various study designs.

Another exciting topic of research in this field is the in vivo CD8⁺ cell imaging using radionuclides with PET which may enable real-time monitoring of patients receiving immunotherapy.

Finally, early career investigators including fellows have many opportunities to be involved in investigating the role of cancer immunotherapy agents. These opportunities include, but are not limited to, conducting preclinical studies expanding the use of immunotherapy agents, conducting more in-depth analyses of patients’ specimens from clinical trials to generate new biomarker-based hypotheses and being part of a multidisciplinary team with members from different fields.