In the first of a four-part series, Jai Balkissoon, vice president of global product development, writes about the increase in immuno-oncology therapies.
Based on oncologists and researchers’ understanding of the tumor microenvironment, are we convinced that combination immunotherapies are better than monotherapy? Combinations with different classes of immunotherapies are showing increased durable responses in multiple tumor types. Perhaps we will find better biomarkers to select effective I-O monotherapy without needing combination therapies.
Rapid-fire development in immuno-oncology
Venture capital continues to flow into I-O, and startups and pharmaceuticals are competing to gain a foothold. More than 240 I-O treatments are currently in development. Cross-industry collaborations among global pharmaceuticals, biotechnology companies, academic centers and community-based oncologists are being announced almost weekly. Meanwhile, patients are clamoring to get new safe and effective drugs faster, and patient advocacy groups and nonprofits are working to raise awareness for important I-O research, riding an unprecedented swell of donations.
Moving toward combination strategies
Like chemotherapy being used as monotherapy followed by combination strategies, this strategy is being applied to immunotherapy. In combination strategies, one agent is used to increase, sustain or complement the response of the other. This may involve a novel agent designed to inhibit immune suppression combined with a backbone checkpoint inhibitor that increases T-cell activation within the tumor. With these combination strategies, we will need to continue to be vigilant and monitor for potential increased toxicities.
We are seeing I-O combinations with chemotherapy, radiation, targeted therapies, antiangiogenic agents, vaccines and other I-O agents. The I-O/I-O combination strategy is very exciting to investigators and one wonders if chemotherapy will eventually become obsolete in certain tumor types. Novel agents that increase tumor associated antigens, activate toll-like receptors (TLRs), increase dendritic cell antigen presentation, inhibit immune suppression and increase the number and activity of tumor-infiltrating lymphocytes (TILs) are being clinically evaluated in concert with checkpoint receptor blockade in clinical trials. Immunotherapy with checkpoint inhibitors (CPIs), which release the “brakes” on the immune system, continue to be used as the “backbone” therapy.
We are seeing older established therapies being combined with the current generation of active agents to increase somatic mutations, neoantigens resulting in better clinical activity. Intratumoral vaccines and oncolytic viruses have emerged again in combination with CPIs with the anticipation of both local and abscopal (distant) effects with increased clinical activity, which we did not observe in older clinical trials. We are also identifying additional biomarkers other than PD-L1 that may be used to predict response to I-O treatment. An example of these are tumor mutation burden (TMB) and mismatch repair deficiency/microsatellite instability-high (MMRD/MSI-H).
Precision medicines targeting genomic aberrations in tumor cells, immunotherapies targeting the antitumor immune response and the intersection of these approaches used in concert all can be optimized by the development of companion diagnostics that identify patients most likely to benefit from them. The goal is to turn “immune deserts” or “cold immune areas” into hot or inflamed areas that have enormous amounts of intratumoral T-cells that can lead to improved response, thus raising the tail of the survival curve.
Jai Balkissoon is a vice president of global product development. Read part two, part three and part four of this series. In addition, the white paper “Addressing key challenges in the clinical development of combination immuno-oncology therapies: A CRO’s perspective” is available for download.