The Pillai lab will explore off-the-shelf, innate natural killer T cell immunotherapies that can be targeted against challenging tumors.
Asha B. Pillai, M.D., a Sylvester Comprehensive Cancer Center researcher and deputy director of translational research for the Department of Pediatrics at the University of Miami Miller School of Medicine, has received two peer-reviewed national foundation grants to fund her work on innate natural killer T (iNKT) cells to provide an off-the-shelf immunotherapy against pediatric cancers. The Accelerating Impact for Hard-to-Treat Cancers Award from the Children’s Cancer Research Fund ($250,000), and the Innovation Grant from the Andrew McDonough B+ Foundation ($150,000), both covering 2022-2024, will support the Pillai research group’s efforts to grow and harness healthy donor iNKT cells to treat challenging pediatric cancers.
“We believe iNKT cells are the right immune mechanism to target aggressive B-cell lymphomas, neuroblastomas, and sarcomas in children,” said Dr. Pillai, who is also associate professor of pediatrics and microbiology and immunology. “These pediatric cancers all have high relapse rates and mortality, therapy-associated complications and limited available treatments.”
While immunotherapies that modulate cytotoxic (killer) T cells have shown some promise, they are expensive, have been plagued by side effects and are not easily retargetable when a patient relapses. In addition, they have so far proven ineffective against solid tumors.
“We believe iNKT cells may offer a more effective immunotherapy alternative,” Dr. Pillai said.
Similar Names, Different Roles
While cytotoxic T cells and innate natural killer T cells share similar names, they are entirely different parts of the immune system. The killer T cells used in CAR-T therapies are part of the body’s adaptive immune response. As a result, T cell receptors are custom designed to attack specific pathogens or tumor cells. They are precise but also less flexible.
As part of the innate immune response, iNKT cells are a potent first line of defense against foreign invaders. As a result, their receptors are less restrictive, giving them flexibility that could allow them to be retrieved from healthy donors and used as off-the-shelf immunotherapies in unrelated people. They could also be redirected therapeutically against relapsed tumors.
In addition, killer T cells bind to protein receptors, which can readily mutate in tumor cells. However, iNKT cells respond to the lipid (fat) cells in cell membranes. When cells become cancerous, they quickly modify these membranes, making them great targets early in cancer progression.
Another positive for iNKT cells is their survivability. Tumor microenvironments are known for their low oxygen and high acidity, a hostile environment for most immune cells. However, iNKT cells can alter their metabolisms under stress, allowing them to survive in these harsh environments.
Broader Therapeutic Firepower
Because iNKT cells are also responsive to the signals often found in solid tumor microenvironments, they could provide therapeutic firepower against them, and other targets CAR-T cells miss. And while each CAR-T dose must be be specifically engineered for each patient, off-the-shelf iNKT treatments could provide broad coverage for many patients, reducing the time it takes to treat them and overall costs.
“The important thing about iNKT cells is that they tend to penetrate these tumor spaces quite well,” Dr. Pillai said. “And because they also regulate the immune system, in addition to directly killing the tumor, they can change the tumor microenvironment and make the tumor more amenable to clearance.”
Dr. Pillai’s team will focus on expanding the availability of iNKT cells and developing nanoparticles that precisely target them against aggressive lymphomas, neuroblastomas, rhabdomyosarcomas and osteosarcomas. She hopes this approach can make this potential therapy widely available.
“While these cells are quite powerful, they are also quite rare,” Dr. Pillai said. “This project is focused on going to the next level to expand them and find novel ways to target them to tumors that can be incredibly difficult to treat. The beauty of having an off-the-shelf therapy is that it is widely available and transportable across centers. Patients could have access to this therapy at community hospitals, not just at cancer centers and major research universities.”