Although ACT has produced dramatic results in some of these patients, not all respond, and the therapy has thus far proven less effective against solid tumors. Optimizing ACT could enable more patients with more types of cancer to benefit from the promising therapy.
Combining 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 an article published online in October by Clinical Cancer Research. They showed that this triple combination treatment (PPiT) doubled the migration of anti-tumor T cells to the tumor site and quadrupled survival in mice compared to ACT alone.
"With this triple combination therapy, many more T cells persisted. That's important for ACT, because the longer the transfused T cells say inside the host to fight tumor cells, the better," says Shikhar Mehrotra, Ph.D., senior author of the article, who is co-scientific director of the oncology and immunotherapy programs in the Department of Surgery at the Medical University of South Carolina and a member of the Hollings Cancer Center.
Of the two agents administered along with ACT as part of this triple combination therapy, PD1 inhibitors are far better known. Clinical successes with checkpoint inhibitors, including PD1 and PDL1inhibitors, ushered in immunotherapy as the fifth pillar of cancer therapy, where it joined the ranks of chemotherapy, surgery, radiotherapy and targeted therapy. PD1 and PDL1 inhibitors take the brakes off of the immune system, enabling its T cells "to see" tumors that had been hiding in plain sight.
In contrast, PIM kinase inhibitors are relative new kids on the block. PIM kinases are proteins that can control many cellular processes, including energy. A clinical roadblock for ACT has been the lack of energy shown by readministered T cells. Mehrotra and his team set out to find whether targeting PIM kinase with an inhibitor could help these readministered cells maintain their energy longer.
"A T cell that starts proliferating is like any person who starts out fresh in the morning with a lot of energy," explains Mehrotra. "Just as the person may have less energy as the day goes on, the T cell can become becomes 'tired' and less effective. We wondered whether the PIM kinase inhibitors could help prevent that from happening."
Mehrotra and his team targeted PIM kinases in T cells to make them act like a specific subtype of T cell, called a central memory T cell. Most ACT trials use rapidly expanding effector T cells (T cells that are ready to attack the tumor), but these T cells often become exhausted when put back in patients. Central memory T cells produce more lasting responses against tumor cells. When Mehrotra and his team blocked PIM kinases in T cells, the cells started acting like memory T cells, as demonstrated by an increase in cell populations that express central memory T cell markers.
"All cells require energy," says Mehrotra. "If you can control the way that T cells use their energy, you could potentially block them from becoming exhausted. In this case, we targeted PIM kinases and show that, in combination with checkpoint therapy and ACT, we get an improvement in T cell response and tumor control."
Indeed, in a mouse model, the triple combination therapy, or PPiT, better controlled the growth of established melanoma than ACT, checkpoint therapy, or PIM kinase inhibitors alone or dual combinations of ACT and a PIM kinase inhibitor or ACT and checkpoint therapy. In addition, more T cells infiltrated the tumor and had decreased expression of PD1, making it harder for tumors to turn them off.
"We ultimately want to be able to implement this therapeutic approach in the clinic," says Mehrotra. "However, we must first explore any potential side effects of the pan-PIM kinase inhibitors and determine whether a more selective inhibitor targeting just one type of PIM kinase might be as effective while posing fewer potential side effects."
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 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 disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.
About Hollings Cancer Center
The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 100 faculty cancer scientists and 20 academic departments. It has an annual research funding portfolio of more than $40 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials.
MEDICAL UNIVERSITY OF SOUTH CAROLINA