Triple Combination Immunotherapy

Illustration depicting three different colored interlocking rings. Beginning in clockwise order: An orange ring labeled Adoptive Cell Transfer (ACT), a teal ring labeled pan-PIM, and a grey ring labeled PD1.

A triple combination immunotherapy quadrupled survival in a preclinical melanoma model

By Julia Lefler

Adoptive cell transfer (ACT) is a promising cancer immunotherapy that involves isolating tumor-targeting T cells from cancer patients, selecting the more active T cells, expanding those in the lab, and then transfusing them back into patients. ACT is already available in the clinic for some diseases, like CAR-T therapy, and many clinical trials of another form of ACT are under way for melanoma treatment.

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.

Combining ACT with a pan-PIM kinase inhibitor and a PD1 inhibitor improves outcomes in a preclinical model, report a team of MUSC investigators in the February issue of 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. The team was led by Shikhar Mehrotra, Ph.D., co-scientific director of the oncology and immunotherapy programs in the Department of Surgery and a Hollings Cancer Center researcher.

“With this triple combination therapy, many more T cells persisted. The longer the transfused T cells stay inside the host to fight tumor cells, the better,” explains Mehrotra.

Of the two agents administered along with ACT as part of this triple combination therapy, PD1 inhibitors are far better understood. PD1 and PDL1 inhibitors, also called checkpoint inhibitors, take the breaks off the immune system, enabling its T cells to “see” tumors that had been hiding in plain sight.

In contrast, PIM kinase inhibitors are relatively 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.

“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 ‘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 central memory T cells, which produce more lasting responses against tumors. 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 into patients. When Mehrotra and his team blocked PIM kinases in T cells, the cells started acting like memory T cells.

The triple combination therapy controlled the growth of established melanoma better 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.”

Adoptive cell transfer (ACT) involves isolating tumor-targeting T cells from cancer patients, selecting the more active T cells, expanding those in the lab, and then transfusing them back into patients.