Avoiding Crashes in the Race Against Cancer With Immunotherapy

Immunotherapy medications have been a wonderful addition to the arsenal of cancer therapeutics. Their use has revolutionized the treatment of many cancers and offers new hope to patients. However, these upsides do not come without downsides.

The underlying concept of current immunotherapy is simple: Immunotherapy drugs help a person’s immune system recog- nize the cancer as an obstacle and mount

a response against it. If fighting cancer is a race and the immune system is a race car, current immunotherapy drugs effectively turn off the brakes. However, at the end of a race, the car will eventually need to use its brakes to stop, and sometimes immu- notherapy cuts the brakes permanently. Crashes do happen.

When its brakes are cut, the immune system may launch an indiscriminate attack, damaging normal tissues in addition to the cancer. Even without immunotherapy, the immune system has a tendency to attack certain organs. Immunotherapy side effects resemble common autoimmune diseases and often affect the gut, lung, endocrine system and skin. Symptoms such as diarrhea, cough, shortness of breath, lack of energy and rashes can be particularly terrible and, when severe, need to be treated early.

HARNESSING THE POWER OF TWO

There have been significant breakthroughs using immunotherapy combinations. Such strategies have focused on pairing two immunotherapy agents (cutting the brakes at two places), using immunotherapy with another potent anti-cancer agent (cutting the brakes and hitting on the gas) and combining immunotherapy with local therapies such as radiation and/or surgery. The success of these combinations has been significantly higher than with a single immu- notherapy agent, but so have the number and severity of toxicities. For example, two commonly used immunotherapy agents, Yervoy (ipilimumab) and Opdivo (nivolumab), have been shown in studies to increase the response rates in melanoma as much as sixfold. This greater effectiveness also brings an increase in toxicity — half of patients experienced severe immune-related side effects, most commonly diarrhea, rash and lack of energy.

THE CONUNDRUM OF TREATING SIDE EFFECTS

Treating immune-related side effects complicates the management of patients with cancer. Immune-blunting drugs such as steroids, the mainstay of treatment for these side effects, halt the immune response, effectively reapplying the brakes, which may unintentionally stop the immune system’s ability to fight the cancer. Furthermore, drug companies are concerned about curtailing the effectiveness of immune agents under investigation, and it’s not infrequent that clinical trials have strict criteria excluding the use of immune-blunting drugs during or prior to patient enrollment. Thus, clinicians may worry that aggressive early treatment of immune-related side effects will curtail an early anti-cancer immune response or limiting clinical trial options.

WHERE WE GO FROM HERE

The study of why immune-related toxicities develop and how to treat them has lagged behind research focusing on the biomarkers that predict effectiveness of immunotherapy. Promising emerging work is beginning to differentiate and study the specific immune cells that are responsible for these side effects. Hopefully, with a deeper understanding of the mechanisms that drive toxicity versus those that drive effectiveness, we will be able to tailor treatment for individual patients, recognize and treat immunotherapy-related complications early, and design immuno- therapy combinations with an eye toward minimizing side effects. Treating cancer with immunotherapy should be considered a delicate balancing act in which we must aim to beat cancer by driving fast but not so fast that we lose control and crash.

Chad Tang, M.D., is an assistant professor of radiation oncology and adjunct assistant professor of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center in Houston.