For nearly 100 years, the treatment of cancer has largely relied on killing tumor cells with nonspecific cytotoxic therapies and radiotherapy. However, this approach is limited and may result in severe systemic toxicities, bystander (killing) effects on normal cells, recurrence of drug-resistant tumor cells (and in some cases the development of new cancers), and the inability to target micrometastases or subclinical disease.

Based on a better understanding of the role of the immune system in the development and progression of cancer, scientists have been successful in advancing novel treatment options, including the production of inhibitory cytokines, recruitment of immunosuppressive immune cells, and upregulation of coinhibitory receptors known as immune checkpoints.

Checkpoint inhibitors work by blocking immune checkpoints (which function as the “brakes” of the immune system). Tumors frequently use and manipulate immune checkpoints to shut down the immune response and protect themselves. Checkpoint inhibitors are “releasing the breaks” and to unleash new immune responses as well as enhance existing responses to promote the elimination of cancer cells. The first immune checkpoint inhibitors, ipilimumab (Yervoy®; Bristol‑Myers Squibb/BMS), was approved by the U.S. Food and Drug Administration in 2011 for the treatment of melanoma.

Following this first approval, the FDA has approved multiple checkpoint inhibitors for the treatment of more than a dozen different types of cancer. And many investigational checkpoint inhibitors are various phases of in clinical development.

And while checkpoint inhibitors have, over the last decade, received considerable and broad interest because of their ability to generate durable responses. However, checkpoint inhibitors may, according to a study published in JAMA Network Open at best lead to responses among less than 13% of patients with cancer in the United States.[1]

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Now, new research has uncovered a mechanism thought to explain why some cancers don’t respond to a widely used form of immunotherapy called “checkpoint inhibitors” or anti-PD-1. The scientists involved in the study also say that they have found a way to fix the problem, paving a way to expand the number of patients who may benefit from the treatment.

The promise it holds
Immunotherapy, which enables the body’s own immune system to attack cancer, has not yet met the promise it holds. While it has been a major advance in the treatment of cancer, up to 85% of patients whose cancer is treated with checkpoint inhibitors don’t benefit, according to estimates.

Samir N. Khleif, M.D., director of The Loop Immuno-Oncology Laboratory at Georgetown Lombardi, led the research team that published new research on checkpoint inhibitors. Photo courtesy: © 2020 Georgetown Lombardi. Used with permission.

In a study published in Nature Immunology, a research team, led by Samir N. Khleif, M.D., director of The Loop Immuno-Oncology Laboratory at Georgetown Lombardi Comprehensive Cancer Center show that the condition of immune cells (T-cells) prior to anti-PD-1 therapy is a crucial determinant for the ability of cancer to respond.

“If the immune cells are not in the appropriately activated state, treatment with anti-PD-1 drives these T cells into a dysfunctional, non-reprogrammable state, inducing resistance to further immune therapy,” explained Khleif, a biomedical scholar and professor of oncology at Georgetown Lombardi, a National Cancer Institute (NCI) designated comprehensive cancer center in Washington, D.C.

In order to prevent the immune system from attacking normal cells, the body has a way of protecting these cells from immune attack.

Releasing the breaks
Cancer cells often adopt this system of checkpoints in order to put the brakes on immune surveillance to protect themselves and grow. Checkpoint inhibitors can release those brakes. These inhibitors target molecules, such as programmed cell death 1 (PD-1), which sits on the surface of a T-cell, and the molecule, PD-ligand 1 (PDL-1) that is present on tumor cells and bind PD-1.

This PD-1/PDL-1 pairing inhibits the normal functioning of T-cells (known as killer CD8), which would otherwise attack the cancer cell. To counteract this process, novel drugs, in the form of antibodies that bind to either PD-1 or PDL-1, work to remove that protection, allowing T-cells to recognize and attack the tumor.

Khleif stated it has been known that the tumors that respond more readily to checkpoint inhibitors are those that have already engaged the immune system, such as melanoma and cancers that express a lot of mutations.

However, scientists wondered why these agents don’t work on immunologically “quiet” tumors. The uncovered a mechanism of action sheds a light on the issue. In addition, the team was also able to find a strategy to overcome such resistance to immunotherapy.

“When we first activate T-cells by using a simple vaccine, or remove the dysfunctional T-cells, we found that the checkpoint inhibitor therapy works better,” Khleif noted

Khleif added that clinical trials are already being developed to confirm these findings in patients, which were made using animal models and patient tumor samples.

Cancer vaccines, based on a patient’s specific tumor, are being explored as a way to prime the tumors – to invigorate T-cell activity and to enhance PD-1 inhibitors.

“In the past, some of these vaccines have been used after checkpoint immunotherapy. Our findings suggest that the vaccines should be used first, or at least in conjunction with anti-PD-1 therapy,” said Khleif.

By examining patient tumor samples from several clinical trials, the researchers have also discovered a signature that identifies patients who would be resistant “biomarker.”

“This might provide an easy and cost-effect prediction method of drug response,” Khleif concluded.

Highlights of Prescribing Information
Ipilimumab (Yervoy®; Bristol‑Myers Squibb/BMS) [Prescribing Information]

[1] Haslam A, Prasad V. Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs. JAMA Netw Open. 2019;2(5):e192535. doi:10.1001/jamanetworkopen.2019.2535 [Article]
[2] Verma V, Shrimali RK, Ahmad S, et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance [published correction appears in Nat Immunol. 2019 Sep 24;:]. Nat Immunol. 2019;20(9):1231-1243. doi:10.1038/s41590-019-0441-y
[3] Verma V, Shrimali RK, Ahmad S, et al. Author Correction: PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance. Nat Immunol. 2019;20(11):1555. doi:10.1038/s41590-019-0519-6 [Article]

Featured image: Laboratories at Georgetown Lombardi Comprehensive Cancer Center, a comprehensive cancer center designated by the National Cancer Institute (NCI). A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington, D.C., area. Photo courtesy: © 2019 – 2020 Georgetown Lombardi Comprehensive Cancer Center

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