Immuno-oncology combinations: raising the tail of the survival curve

Abstract

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Keywords: CTLA4; Combination drug therapy; PD-1; PD-L1; biomarkers; clinical trials; immunotherapy; oncology.

Figure1

Current immunotherapeutic strategies with checkpoint inhibition.

Figure2

Future combination strategies with checkpoint inhibition. Multiple strategies can be used in combination with checkpoint inhibition to enhance the antitumor function of the immune system as shown. Immunogenic cell death can be promoted by chemotherapy, radiotherapy, targeted therapies as well as novel agents. Antigen presentation can be enhanced using vaccine therapies, immune adjuvants and other novel agents. Immune-suppression can be reduced or eliminated by attenuating suppressor cells and the microenvironment milieu and effector T cell function can be enhanced. TRAIL-R, TRAIL-receptor; TNF-SF, tumor necrosis factor super family; IDO1, indoleamine 2,3-dioxygenase 1; CXCR2, chemokine (C-X-C Motif) receptor 2; LAG-3, lymphocyte-activation gene 3; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; GM-CSF, granulocyte-macrophage colony-stimulating factor