The next frontier for CAR T cell therapy in blood cancers

Chimeric Antigen Receptor (CAR) T cell therapy was pioneered at Penn Medicine, where researcher-physicians began clinical trials of the personalized cell therapy in 2010—seven years before the U.S. Food and Drug Administration approved Kymriah, the first CAR T treatment product. In the decade and a half since treating the first patient, Penn physician-scientists have performed more than 760 CAR T therapy infusions.

Penn physician-scientists were also the first to successfully treat cytokine release syndrome (CRS), a widespread inflammatory response that often accompanies CAR T therapy. They continue to optimize the therapy while gaining a wealth of knowledge about how to prevent and manage such treatment side effects. Currently, CAR T is being evaluated at Penn Medicine in earlier-line settings and next-generation products are being investigated to make the treatment more efficient and effective.

“Using patients’ own immune cells has been a revolution in how we treat cancer,” says Noelle Frey, MD, MS, Director of Clinical Cellular Therapy, Center for Cell Therapy and Transplant at Penn Medicine. “One of the most exciting things about CAR T therapy is that it often works when traditional therapies don’t.”

Cell therapy expands into more settings

CAR T therapies are FDA-approved for treating relapsed or refractory blood cancers, including multiple myeloma, acute lymphoblastic leukemia (ALL), and some non-Hodgkin lymphomas (NHL). In ALL and NHL, CAR T therapy can offer durable, potentially curative remissions. “Before the advent of CAR T therapy, there weren’t many effective treatment options for patients with relapsed disease,” says Dr. Frey. “Now we can offer something with curative potential.”

In patients with relapsed or refractory diffuse large B-cell lymphoma, for instance, traditional treatments such as chemotherapy and bone marrow transplant produced survival rates of around 5 to 10 percent, notes B-cell lymphoma specialist Michael R. Cook, MD, Assistant Professor of Clinical Medicine (Hematology-Oncology) at Penn Medicine. “Now, with CAR T cell therapy, the cure rate in the relapsed and refractory setting is around 40 percent,” Dr. Cook says. “We have further to go, but that benchmark is impressively higher.”

Building on gains in relapsed and refractory disease, researchers continue to push the boundaries of CAR T. Currently, Penn Medicine has nearly three dozen clinical trials studying the therapy, including studies to evaluate the treatment for myelodysplastic syndrome and acute myeloid leukemia (AML), as well as some solid tumors.

Researchers are also exploring the treatment in earlier stages of disease. “As helpful as CAR T therapy has been in the relapsed/refractory setting, we anticipate it may be even more beneficial in up-front settings—and that’s a very active area of clinical research,” Dr. Frey says, adding that access to clinical trials is a big reason she encourages physicians to refer patients to Penn early in the course of their blood cancer treatment.

Designing the next generation of CAR T therapy

As clinical research continues, Penn Medicine cell therapy scientists are actively developing the next generation of CAR T treatment products. Some active areas of research include:

Fighting T cells with T cells

Although CAR T therapy has become a standard of care in B-cell lymphomas, T cell malignancies present an obvious challenge. Because CAR T cells are themselves T cells, they can commit a sort of fratricide, killing each other. To overcome that challenge, Penn Medicine researchers are leading a clinical trial to test CAR T cells engineered to lack the cell surface protein CD5, a biomarker present in a subset of T cell lymphoma patients. The modified CAR T cells are designed to target CD5, allowing them to attack malignant cells without destroying one another.

This approach addresses the T cell fratricide issue, a serious concern of cell therapy for T cell lymphomas that can lead to T cell aplasia—a potentially serious complication that can affect the body's ability to fight off infections. To avoid T cell aplasia, researchers harvest patients’ healthy T cells and genetically reduce CD5 expression before reinfusing them, creating a pool of healthy cells that can evade CAR T cells.

Armored CAR T cells to improve treatment response

While many patients have a strong positive clinical response to CAR T therapy, a subset of patients do not respond to the therapy. Researchers are still trying to understand why, but there is evidence that the inflammatory milieu in the cancer microenvironment may be a factor. To address it, Penn Medicine scientists have created a so-called “armored CAR” T cell that secretes the immune-modulating cytokine interleukin-18.

In a small Phase I study published in the New England Journal of Medicine, researchers found that the treatment had a similar safety profile to other CAR T treatments and showed promising efficacy at low cell doses in patients with lymphoma who had not responded to previous CAR T therapy. Research is ongoing to develop and assess this approach.

Off-the-shelf CAR T therapy

Genetically engineering and manufacturing customized cell therapy products for each patient is a time- and resource-intensive process. “One limitation of CAR T therapy is that patients sometimes need treatment urgently, and they can’t wait the three or four weeks that it takes for CAR T cells to be manufactured,” says Alfred L. Garfall, MD, Director of Autologous Hematopoietic Stem Cell Transplantation and Section Chief of Myeloma at Penn Medicine. “One way to get around that is to create CAR T cells from a healthy person, stock them in the freezer, and thaw them to give to patients as soon as they’re needed.”

Hoping to make such off-the-shelf cell therapy possible, researchers are creating allogeneic CAR T cells from healthy donors, engineered to prevent immune rejection or graft-versus-host effects of the T cells against the patient. Penn Medicine is one of numerous sites now testing this approach in a Phase I trial in patients with multiple myeloma.

Immunotherapy expertise: Preventing and managing complications of CAR T therapy

While CAR T therapy can deliver dramatic and durable responses, it carries the risk of serious side effects, including inflammatory syndromes and neurotoxicity. In the early days of CAR T therapy, those risks made some physicians hesitant to consider the treatment for older adults and patients with comorbidities. As experts have learned to manage side effects, however, the therapy has become safer for more patients. Unlike bone marrow transplants, which are rarely performed past age 75, CAR T therapy has been used to treat people in their 90s.

“At Penn Medicine, our disease experts are also CAR T therapy experts, because it has been part of our institution for so long,” says Dr. Frey. “We’ve been leading clinical trials of this therapy for years, and we’ve made leaps and bounds in terms of learning to predict and manage treatment toxicities.”

In patients at higher risk of severe side effects, for example, physicians might offer preventive therapies, such as steroids, to reduce the risk of neurotoxicity. A fuller understanding of how to prevent and manage side effects has allowed us to safely shift some cell therapy infusions to outpatient settings.

CAR T therapy in the community

At Penn Medicine, more than half of CAR T infusions are being administered in the outpatient setting. Patients enjoy the convenience of outpatient treatment while having access to the Oncology Evaluation Center at the Hospital of the University of Pennsylvania, which functions as a 24/7 urgent care resource for cancer patients. Patients also have access to a CAR T therapy hotline where they can speak to experts around the clock if they experience side effects or have questions or concerns.

As the risks of CAR T therapy diminish, and opportunities for cell therapy continue to expand, the pool of potential candidates keeps growing. “We welcome referrals to consider whether CAR T therapy might have a place in the treatment plan, especially for patients with relapsed disease,” Dr. Frey says. “Even when chemotherapy and other treatments have stopped working, CAR T therapy offers a potential way forward.”

Referrals and Consultations

To refer a patient to the Penn Medicine Division of Hematology and Oncology, call 877-937-7366, or refer a patient online.