New understanding of how to harness the immune system to fight cancer

WASHINGTON – Georgetown University’s Lombardi Comprehensive Cancer Center researchers have identified a new way to reprogram T cells, which are infection and tumor-fighting white blood cells, so that they have a superior memory, thereby making them more effective in killing cancer cells.

The finding, published January 12, 2026, in Nature Immunology, amplifies a known strategy of blocking the cellular activity of PARP, an enzyme that detects DNA abnormalities in cells and repairs them.       

“This opens the door to a new area of research in understanding how our immune system works, and as importantly, it opens the way for the development of new strategies for the treatment of cancer,” says Samir N. Khleif, MD, director of The Center for Advanced Immunotherapy Research and the director of Loop Immuno-Oncology Research Laboratory at Georgetown’s Lombardi.

When PARP functions in overdrive it helps fuel cancer growth and drugs used to block PARP are called PARP inhibitors. Georgetown researchers found that inhibiting PARP with such drugs in a key group of immune cells, called CD8 T cells, can significantly enhance the function of these cells and boost the body’s immune response against tumors.    

In their in vitro and mouse studies, the researchers determined that PARP inhibition helps CD8 T cells develop into a superior memory form, that they become activated more effectively, and that they attack cancer cells more forcefully. This process is achieved by reprogramming the cells’ metabolism, making them stronger and longer lasting in the fight against cancer. In essence, these enhanced memory T cells show better recall and anti-tumor activity.

PARP inhibitors can be effective in treating several cancers that carry specific mutations, such as BRCA mutations, that lead to defects in DNA repair. Importantly, in this new finding, the investigators identified a role for these drugs in enhancing the anti-tumor immune effect regardless of the presence of specific DNA mutations in the cancer.      

According to Khleif, this finding expands the potential use of PARP inhibitors into many types of cancer and suggests that PARP inhibitors can be used in combination with immunotherapy to widen their utility and potentially achieve higher efficacy.

“The new T cells that we identified are superior memory T cells. They exhibit a stronger response to foreign antigens and possess prolonged survival, leading to greater and more robust anti-tumor activity. They are crucial for strong, long-lasting anti-tumor immune responses, which can be linked to better patient outcomes,” notes Khleif. “By promoting these T cells, PARP inhibitors could potentially make cancer immunotherapy more effective.”

In previous research published in Nature Immunology, Khleif and his team discovered another T cell reprogramming strategy by targeting the a pathway different than the PARP pathway. They found that the MEK pathway could be also used in different settings for enhancing cancer therapy.

“Together, our two recent studies pave the way for a new and important field of investigation, which is targeting signaling pathways by using small molecules for reprogramming T cells into novel and specific subtypes,” says Khleif.

Small molecule inhibitors, such as olaparib, which is one of the drugs that the investigators used in their experiments, and which is currently used to treat people with certain forms of cancer, can easily enter cells, unlike large antibodies, to hit intracellular pathway targets. The effects of such inhibitors can be precisely tuned or reversed by changing their concentrations and they are also easy to administer as they can be delivered orally.

For their next step, the scientists hope to translate this discovery into strategies that could be tested in clinical trials to treat patients with difficult-to-treat cancers. 

For example, there are currently no clinical trials combining PARP inhibitors with ACT (adoptive cell therapy) or CAR (chimeric antigen receptor)-T cells therapies, which are personalized types of immunotherapies.  

Khleif and his colleagues are exploring the possibility of developing such a clinical trial for patients with ovarian, breast or prostate cancers using these combination therapies.

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In addition to Khleif, the other authors at Lombardi include Wael Traboulsi, Pankaj Gaur, Subhadip Kundu, Zainab Ramlaoui, Christopher Priestly-Milianta, Aishwariya Iyengar, Nour Shobaki, Dareen Sarhan, Mikayel Mkrtichyan, Seema Gupta and Vivek Verma. Min-Jung Lee, Jung-Min Lee and George N. Pavlakis are at the National Cancer Institute, NIH. Viia E. Valge-Archer and Simon T. Barry are at AstraZeneca Oncology R&D, Cambridge, United Kingdom. Verma is now at the Masonic Cancer Center, University of Minnesota, Minneapolis, MN.

Khleif, Gupta, Traboulsi and Gaur are inventors on patent applications related to work on the methods for producing a super central memory CD8 T cell subtype by poly(ADP-ribose) polymerase (PARP) inhibition and uses thereof. Khleif is a founder of Georgiamune LLC and Precision Immunotherapeutics; a consultant or a member of the Board Georgiamune and Emerald, and member of Advisory Board of Nectin Therapeutics, Northwest Biotherapeutics, Stemline Therapeutics Inc., and UAMS Winthrop P. Rockefeller Cancer Institute; has research support from AstraZeneca, BristolMyers Squibb, Johnson & Johnson, and Merck; has Equity (Options) in  KAHR Medical, Nectin Therapeutics, Northwest Biotherapeutics, and SandboxAQ, Inc. Valge-Archer and Barry are employees and shareholders of AstraZeneca. The remaining authors declare no competing interests.

This work was supported by Karen and Fred Schaufeld and Michelle and David Joubran through the Center for Advanced Immunotherapy Research and by Jeannie and Tony Loop for their generous support to the Loop Immuno-oncology Research Laboratory. Support also came from NIH grants P30-CA051008 and S10OD016213.