Study Shows Why a Common Form of Immunotherapy Fails, and Suggests Solution

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Samir Khleif
Samir N. Khleif, MD, director of The Loop Immuno-Oncology Laboratory at Georgetown Lombardi, led the research team that published new research on checkpoint inhibitors.

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Karen Teber

WASHINGTON (August 2, 2019) — 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. In addition, the scientists say they have found a way to fix the problem, paving a way to expand the number of patients who may benefit from the treatment.

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 percent of patients whose cancer is treated with checkpoint inhibitors don’t benefit, according to estimates.

In a new study published online July 29 in Nature Immunology, a research team, led by Samir N. Khleif, MD, director of The Tony and Jeannie Loop Immuno-Oncology Laboratory at Georgetown Lombardi Comprehensive Cancer Center, shows 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,” Khleif explains.  

In order to prevent the immune system from attacking normal cells, the body has a way of protecting these cells from immune attack. Cancer cells often adopt this system of checkpoints in order to put the brakes on immune surveillance to protect themselves and grow. Checkpoint inhibitors release those brakes.

These inhibitors target molecules, such as PD-1 (programmed cell death 1), which sits on the surface of a T cell, and the molecule, PDL-1 (PD-ligand 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. So 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 says 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. The question has been why the agents don’t work on immunologically “quiet” tumors. This discovery now sheds a light on the issue.

The team also was 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,” says Khleif, biomedical scholar and professor of oncology at Georgetown Lombardi. 

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

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

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

Co-authors include: Vivek Verma, PhD, Rahul Nandre, PhD, Pankaj Gaur, PhD, Seema Gupta, PhD, and Jose Lopez, BS, from The Loop Immuno-oncology Laboratory, Georgetown Lombardi Comprehensive Cancer Center; Ming Tan, PhD, from Georgetown University; Rajeev K Shrimali, PhD, and Jennifer A. Wargo, MD, MMSc, at University of Texas MD Anderson Cancer Center; Shamim Ahmad, PhD, at Five Prime Therapeutics Inc., South San Francisco; John E. Janik, MD, at Incyte Inc., Wilmington, DE; Mikayel Mkrtichyanat, PhD, at  Biotherapeutics, Agoura Hills, CA; Winjie Dai, Hua Wang, MD, and Sumin Lu, MD, at Georgia Cancer Center, Augusta University, GA; Moshe Sade-Feldman, PhD, Stacey L. Bjorgaard, Nir Hacohen, PhD, Keith T. Flaherty, MD, Genevieve M. Boland, MD, PhD, Gad Getz, PhD, and Ryan J. Sullivan, MD, at Massachusetts General Hospital Cancer Center; Keren Yizhak, PhD, at Broad Institute of Massachusetts Institute of Technology and Harvard; Scott A. Hammond, PhD, at MedImmune LLC, Gaithersburg, MD; Jingjing Qi, MBBE, Phillip Wong, PhD, Taha Merghoub, PhD, and Jedd Wolchok, MD, PhD, at Memorial Sloan Kettering Cancer Center.

This research was funded in part by grants from the National Institutes of Health (P30CA008748, R01CA056821, R01CA208756), Swim Across America, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy and Virginia B. Squiers Foundation, the Cancer Research Institute, and Adelson Medical Research Foundation. Additional support was provided by the Georgia Cancer Center, Georgetown Lombardi Comprehensive Cancer Center (P30 CA 051008), and the Ludwig Center for Cancer Immunotherapy.

Khleif, Gupta and Verma are inventors on a patent application related to technology described in this paper. Khleif reports the following disclosures: an honorarium from Syndax, IO Biotech, BioLine, Northwest Biotherapeutics, Advaxis, EMD Serono, GSK, UbiVac, McKinsey, AstraZeneca and Lycera; stock or ownership interest in Advaxis, GeorgiaImmune, IO Biotech and Northwest Therapeutics; consultant work for Syndax, IO Biotech, BioLine, Kahr, PDS Biotechnology, AstraZeneca, CytomX, NewLink Genetics, AratingaBio, CanImGuide and Lycera; and board membership of Advaxis. Khleif reports research contracts with Syndax, IO Biotech, BioLine, AstraZeneca, MedImmune and Lycera. Additional disclosures of other authors are listed in the published study.

About Georgetown Lombardi Comprehensive Cancer Center (new window)
Georgetown Lombardi Comprehensive Cancer Center is designated by the National Cancer Institute (NCI) as a comprehensive cancer center. A part of Georgetown University Medical Center, Georgetown Lombardi is the only comprehensive cancer center in the Washington, D.C., area. It serves as the research engine for MedStar Health, Georgetown University’s clinical partner. Georgetown Lombardi is also an NCI recognized consortium with John Theurer Cancer Center/Hackensack Meridian Health in Bergen County, N.J. The consortium reflects an integrated cancer research enterprise with scientists and clinicians from both locations. Georgetown Lombardi seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic, translational and clinical research, patient care, community education and outreach to service communities throughout the Washington region, while its consortium member John Theurer Cancer Center/Hackensack Meridian Health serves communities in northern New Jersey. Georgetown Lombardi is supported in part by a National Cancer Institute Cancer Center Support Grant (P30CA051008). Connect with Georgetown Lombardi on Facebook ( (new window)) and Twitter (@LombardiCancer (new window)).