Triple-combination cancer immunotherapy improves results in preclinical melanoma model

Adoptive Cell Transfer (ACT) is a promising cancer immunotherapy that consists of isolating T cells from cancer patients that are able to target their tumor, selecting the most active T cells and developing them in the laboratory, and transfusing them back to patients. . ACT is already available clinically for some diseases – CAR T treatment, a form of ACT, has been approved by the FDA in 2017 for children with acute lymphoblastic leukemia and adults with advanced lymphoma – and many Clinical trials of another form of ACT are ongoing in melanoma.

Although ACT has produced dramatic results in some of these patients, not all of them respond and the treatment has so far proven less effective against solid tumors. Optimizing ACT may allow more patients with more types of cancer to benefit from the promising treatment.

The association of ACT with a pan-PIM kinase inhibitor and a PD1 inhibitor improves outcomes in a preclinical model, report researchers at the Medical University of South Carolina (MUSC) in a published article online in october by Clinical research on cancer. They showed that this triple combination treatment (PPiT) doubled the migration of antitumor T lymphocytes to the tumor site and allowed a quadrupled survival in mice compared with ACT alone.

"Thanks to this triple therapy, many other T cells have persisted – it's important for ACT because the better it is, the more transfused T cells usually fight tumor cells, the better." Is, "says Shikhar Mehrotra, Ph.D., senior author of the article, who is co-scientific director of the oncology and immunotherapy programs of the Department of Surgery of the United States. Medical University of South Carolina and a member of the Hollings Cancer Center.

Of the two agents given with ACT as part of this triple therapy, PD1 inhibitors are much better known. The clinical successes achieved with the control point inhibitors, including the PD1 and PDL1 inhibitors, have made immunotherapy the fifth pillar of cancer therapy, where she joined the ranks of chemotherapy, surgery, radiotherapy and targeted therapy. Inhibitors of PD1 and PDL1 slow down the immune system, allowing its T cells to "see" the tumors that were hidden in view.

In contrast, PIM kinase inhibitors are relatively new on the market. PIM kinases are proteins that can control many cellular processes, including energy. One of the clinical barriers to ACT is the lack of energy demonstrated by re-administered T cells. Mehrotra and his team have investigated whether targeting PIM kinase with an inhibitor could help these re-administered cells retain their energy longer.

"A T cell that starts to proliferate, it's like anyone who starts in the morning with a lot of energy," says Mehrotra. "Just as the person may have less energy as the day progresses, T cells can become" tired "and less effective.We wondered if inhibitors of PIM kinase could help prevent that this happens. "

Mehrotra and his team have targeted PIM kinases in T cells to act as a specific T cell subtype, called a T cell with a central memory. Most ACT trials use rapidly expanding effector T cells (T cells that are ready to attack the tumor), but these T cells often deplete when they are replaced in patients. Central memory T cells produce more durable responses against tumor cells. When Mehrotra and his team blocked PIM kinases in T cells, they began to act as memory T cells, as evidenced by an increase in the number of cell populations expressing central markers of memory T cells.

"All cells need energy," Mehrotra says. "If you can control how T cells use their energy, you could prevent them from depleting it.In this case, we targeted the PIM kinases and showed that in combination with the control point therapy and the ACT, we get an improved T cell response and tumor control. "

Indeed, in a mouse model, triple therapy, or PPiT, better controlled growth of established melanoma than ACT, control point therapy or PIM kinase inhibitors alone or a dual combination of ACT and an inhibitor of PIM kinase or ACT and checkpoint therapy. In addition, more T cells infiltrated the tumor and reduced the expression of PD1, making it more difficult for them to be extinguished by tumors.

"Ultimately we want to be able to implement this therapeutic approach in the clinic," said Mehrotra. "However, we must first explore potential side effects of pan-PIM kinase inhibitors and determine if a more selective inhibitor targeting a single type of PIM kinase could be as effective while resulting in fewer potential side effects." . "

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About MUSC

Founded in 1824 in Charleston, the South Carolina Medical University is the oldest medical school in the South. MUSC continues today the tradition of excellence in education, research and patient care. MUSC educates and trains more than 3,000 students and residents and has close to 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $ 2.2 billion. MUSC operates a 700-bed medical center, which includes a nationally-recognized children's hospital, the Ashley River Tower (cardiovascular, digestive and surgical diseases), the Hollings Cancer Center (a designated center of the National Cancer Institute), and Institute of Psychiatry. For more information on academic programs or clinical services, visit musc.edu. For more information on inpatient services, visit muschealth.org.

About the Hollings Cancer Center

The Hollings Cancer Center at the Medical University of South Carolina is a cancer center designated by the National Cancer Institute and the largest university cancer research program in South Carolina. The cancer center has more than 100 scientists and 20 university departments. It has an annual funding portfolio of more than $ 40 million in research and a commitment to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques in multidisciplinary clinics including surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists for more than 200 treatments. clinical tests. For more information, visit http: // www.hollingscancercenter.org