Trying to Improve the Odds of Cancer Immunotherapy

Checkpoint inhibitors have led to remarkable responses in a small percentage of patients. Could combining them with other drugs improve the odds?

Immune checkpoint inhibitors have led to a paradigm shift in the approach to treating a growing list of cancer types. Therapies such as Keytruda, which blocks PD-1/PD-L1 signaling to release the brake on the immune system, enhancing tumor killing, have had enormous success with some patients showing remarkable and long-lasting responses. The problem is only about a fifth of patients respond to checkpoint inhibitor monotherapy. Hence, the race is on to boost the response rates by partnering leading checkpoint inhibitors with established therapies (such as chemotherapy) and those which target novel mechanisms.

With around 30 checkpoint inhibitor targets known, many of the new trials aim to block two or more checkpoint receptors such as CTLA-4 and LAG-3. At the top of the priority list are combinations that show individual success and early signs suggest this is a promising approach. A trial with the FDA-approved Yervoy (anti-CTLA-4) and Opdivo (anti-PD-1) showed a two-year survival rate for melanoma patients treated with both drugs at 69%, compared to 53% on Yervoy alone.

As the field moves forwards, there is clearly a great deal of interest in targets beyond the classic immune checkpoint receptors. Importantly, there are a large number of such targets. For example, IDO, another negative regulator of the immune system is primarily expressed in tumor cells or activated innate cells. When active, it creates an immunosuppressive microenvironment enabling tumor cells to evade the immune system. IDO enzymatic activity can be blocked by the first-in-class small molecule; Epacadostat. A 600-patient phase III trial (KEYNOTE-252/ECHO-301) combining Epacadostat and Keytruda was eagerly awaited, particularly considering the success of a recently released Phase I/II study. Unfortunately, the trial was stopped for futility in April after it failed to improve survival for melanoma patients compared to Keytruda alone.

Further from the clinic, however, and gathering momentum, is an alternative strategy combining checkpoint inhibitors with drugs or antibodies that target T regulatory cells (Tregs), such as anti- CCR4 or CD25. Tregs are well known to infiltrate the tumor microenvironment and suppress tumor-killing cytotoxic T cells. In mouse models, combining drugs that supress Treg function with checkpoint inhibitors improved the effectiveness of individual immunotherapies, studies have shown..

The key to combination success is likely to lie in finding the right combination for the right cancer. Understanding the cellular and molecular mechanisms through basic and preclinical research will help to get us to get there sooner.

An earlier version of this post appeared on the blog site of KWS BioTest, now part of Charles River Laboratories.

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