CAR T Cells and Beyond: An Exciting Future for Immunotherapy

Guenther Koehne, MD, PhD

Harnessing the ability of the body’s own immune system, particularly with the use of chimeric antigen receptor (CAR) T cells, has already made a significant impact on the survival of patients with some hematologic malignancies. Perhaps the most exciting news, however, is that what we have learned in the infancy of our work with CAR T-cell therapy (which first received FDA approval in 2017), along with new information gleaned from ongoing research and clinical trials, is helping us develop next-generation immunotherapy treatments that are specifically tailored to the individual. In addition, it is expanding the types of cancers and patients that can be treated with CAR T cells.

At Miami Cancer Institute’s Second Annual Summit of the Americas on Immunotherapies for Hematologic Malignancies, held May 14, 2021, some of the nation’s top experts shared the latest advances. For example, Robert Soiffer, MD, from Dana Farber Cancer Institute, reviewed real-world results published in the last year that show CR rates for patients with diffuse large B-cell lymphoma ranging from 40 to 64 percent and ORR rates ranging from 59 to 82 percent (from Jacobson, Nastoupil, Pasquini and others).

As we adjust conditioning regimens, induction timing and dosing levels, we continue to have many questions, but are greatly encouraged. Is it possible that one day in the future, we will use CAR T cells instead of transplantation or as a bridge to transplantation? Will CAR T cells or other CAR cells replace chemotherapy for some? Time will tell.

Paul Lin, MD, of MD Anderson Cancer Center, spoke on CAR cells being introduced into other immune effector cells. And he showed that CAR-NK (natural killer) cells can be used to treat DLBCL, and that by adding a checkpoint inhibitor, a booster effect is felt.¹ While scientists are looking at the benefits of many cells that bolster the immune system, research into CAR-NK cells is advancing quickly and it may be that CAR-NK, with lower toxicity and off-the-shelf availability, will eventually provide an additional CAR immunotherapy approach.

At the Herbert Wertheim College of Medicine at Florida International University, Robert Sackstein, MD, PhD, has shown that inducing expression of E-selectin ligand on CAR T-cells can improve the acceleration of the genetically altered cells directly to the tumor site.² Among the benefits are the ability to induce a complete remission using fewer cells, and thereby reducing toxicities.

The issue of toxicity, particularly among older and more frail patients, is an interest of Wendy Stock, MD, of the University of Chicago. She reported that her work in using immunotherapy drugs rather than standard chemotherapy in older adults with acute lymphoblastic leukemia is moving immune targeting to the frontline.³

While the volume and variety of information coming from current studies seems overwhelming, it is what is changing the cancer care environment today. Many of these studies are aimed at patients with very complex and relapsing disease. These advances, that also include a better understanding of how biomarkers relate to treatment response, are leading us to significant improvements in patient care.

_References

_{1. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Accessed May 13, 2021. https://bit.ly/3oV251u}

_{2. Glycoengineering of chimeric antigen receptor (CAR) T-cells to enforce E-selectin binding. Biol Chem. 2019;29;294(48):18465-18474. doi: 10.1074/jbc.RA119.011134}

_{3. Patel AA, Heng J, Dworkin E, et al. Expanding use of a modified pediatric intensive regimen for acute lymphoblastic leukemia (ALL) into an older adult population: feasibility and efficacy results. Blood. 2020: 136 (Suppl 1): 41–42. doi: 10.1182/blood-2020-138967}