Georgetown University researchers have found a way to reprogram key immune cells so they remember and attack cancer more powerfully and for longer. The lab discovery could expand the use of existing PARP drugs and strengthen cutting-edge immunotherapies.
Researchers at Georgetown University’s Lombardi Comprehensive Cancer Center have discovered a way to turn a familiar class of cancer drugs into powerful tools for supercharging the immune system.
In experiments using cells in the lab and mouse models, the team showed that drugs known as PARP inhibitors can reprogram a crucial group of immune cells, called CD8 T cells, so they remember tumors better and attack them more forcefully and for longer periods of time.
The work, published today in the journal Nature Immunology, suggests that medicines already used to treat some cancers could be repurposed to make immunotherapies more effective across a wider range of tumors.
The findings point to a new way of thinking about how to harness the body’s own defenses, according to Samir N. Khleif, director of The Center for Advanced Immunotherapy Research and the director of Loop Immuno-Oncology Research Laboratory at Georgetown’s Lombardi.
“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,” Khleif said in a news release.
PARP (short for poly[ADP-ribose] polymerase) is an enzyme that helps cells detect and repair damaged DNA. When PARP is overactive in cancer cells, it can help tumors survive and grow. PARP inhibitors, such as olaparib, are designed to block this repair process, causing cancer cells with certain DNA repair defects to die.
So far, PARP inhibitors have mainly been used in cancers with specific mutations, such as BRCA mutations, that make tumor cells especially dependent on PARP. The new study adds another dimension: rather than focusing only on the cancer cells, the researchers looked at what happens when PARP is blocked in immune cells.
They found that inhibiting PARP in CD8 T cells — the white blood cells that recognize and kill infected or cancerous cells — dramatically improved how these cells functioned against tumors.
In the lab and in mice, PARP inhibition nudged CD8 T cells into a special “memory” state. Memory T cells are the immune system’s long-term sentinels. After an initial encounter with a virus, bacterium or tumor, they stick around, ready to respond quickly if the threat returns.
The Georgetown team showed that PARP-blocked CD8 T cells developed into a superior memory form. These reprogrammed cells activated more effectively, persisted longer and mounted stronger attacks on cancer cells. The shift was driven by changes in the cells’ metabolism and gene activity, essentially rewiring them to be tougher and longer lasting in the fight against cancer.
Khleif described these cells as a particularly potent type of memory T cell.
“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,” he added. “By promoting these T cells, PARP inhibitors could potentially make cancer immunotherapy more effective.”
One important implication is that PARP inhibitors might help the immune system fight tumors even when the cancer does not carry the classic DNA repair mutations that make it sensitive to these drugs. That could expand the use of PARP inhibitors beyond their current niche and into many more cancer types.
It also opens the possibility of combining PARP inhibitors with existing immunotherapies. Today’s cancer immunotherapy toolbox includes drugs that take the brakes off T cells, as well as personalized approaches like adoptive cell therapy (ACT) and chimeric antigen receptor (CAR) T-cell therapy, where a patient’s own T cells are engineered and reinfused to target cancer.
So far, there are no clinical trials that pair PARP inhibitors with ACT or CAR T-cell therapies. Based on their findings, Khleif and his colleagues are exploring the design of such trials for patients with difficult-to-treat cancers, including ovarian, breast and prostate cancers.
The new study builds on earlier work from the same group, also published in Nature Immunology, in which they showed that targeting a different signaling route in T cells, known as the MEK pathway, could also reprogram T cells and enhance cancer treatment in certain settings.
“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,” Khleif added.
Small molecule inhibitors like olaparib are attractive tools for this kind of fine-tuning. Unlike large antibody drugs, they can slip easily into cells and reach targets inside. Their effects can be adjusted or reversed by changing the dose, and many can be taken by mouth, making them relatively convenient for patients.
In this case, the researchers used PARP inhibitors as small-molecule switches to shape the fate of CD8 T cells, steering them toward a central memory state that appears especially valuable for long-term tumor control.
The study was an experimental, preclinical effort using animal models, so it does not yet prove that the same approach will work in people. But it lays the groundwork for translating the concept into human trials and offers a roadmap for how to test these combinations safely.
If the strategy holds up in patients, it could help address a major challenge in oncology: many people either do not respond to immunotherapy or see their responses fade over time. Strengthening and extending T-cell memory could be one way to turn more of those initial responses into lasting remissions.
The research involved scientists at Georgetown Lombardi, the National Cancer Institute at the National Institutes of Health, and AstraZeneca Oncology R&D in the UK.
Several authors, including Khleif, are inventors on patent applications related to methods for producing enhanced central memory CD8 T cells using PARP inhibition, and some have financial relationships with biotechnology and pharmaceutical companies. The remaining authors reported no competing interests.
For now, the findings add momentum to a broader trend in cancer research: rather than relying on one type of treatment, scientists are learning how to combine targeted drugs and immunotherapies in smarter ways, with the goal of training the immune system not just to attack tumors today, but to remember them for years to come.