Research Project Aims to Make CAR-T-cell Therapy Safer and More Effective

Brian Hess, MD

A new project led by researchers at MUSC Hollings Cancer Center could significantly decrease the side effects associated with CAR-T-cell therapy and make the treatment available to more patients who could benefit.

Led by Hollings hematologist and oncologist Brian Hess, M.D., and Shikhar Mehrotra, Ph.D., co-leader of Hollings’ Cancer Immunology Program, the project involves manufacturing a “purified” version of the CAR-T-cells that are currently used to treat patients with certain types of lymphoma and leukemia to reduce the side effects associated with treatment and potentially make the treatment more effective. The therapy will be given to patients as part of a clinical trial, including lymphoma and leukemia patients who don’t currently have approval from the Food and Drug Administration (FDA) to receive CAR-T.

Shikhar Mehrotra, PhD

The project is supported in part by a new $50,000 grant from LOWVELO, Hollings’ annual community event that rallies everyone together to raise money for lifesaving cancer research. The CAR-T-cell program is one of the first programs to benefit from the fund.

“The grant we’ve received from LOWVELO is a really great start to help us to get this project off the ground and to help us to treat our first patient,” Hess said.

CAR-T-cell therapy works by collecting a patient’s T-cells, genetically modifying these cells to identify specific targets (CD19) on cancer cells and then infusing them back into patients to fight their disease.

CD19 directed CAR-T-cell therapy is currently approved for B-cell acute lymphoblastic leukemia (B-ALL) patients age 25 or younger and adult patients with specific subtypes of CD19 expressing non-Hodgkin lymphoma. The clinical trial at Hollings will be open to adult patients with B-ALL up to any age and certain patients with CD19 expressing non-Hodgkin lymphoma both who are and are not currently eligible to receive the FDA-approved products.

As part of this trial, researchers at Hollings are collaborating with Loyola University Chicago researchers to build on their existing technology by utilizing a specific cytokine (protein) IL-12 in the manufacturing process of the CAR-T-cell product. In September 2018, Loyola and Loyola Medicine received a $250,000 grant from the Leukemia Research Foundation to develop purer, less toxic CAR-T-cells to treat leukemia and lymphoma.

Mehrotra, who also is the scientific director of MUSC’s FACT-accredited Clean Cell Therapy Unit, said the MUSC project for developing CD19 CAR-T was initiated through a collaboration with Michael Nishimura, Ph.D., at Loyola, who worked with the researchers to generate CD19 CAR-T-cells at MUSC’s clean-cell facility.

“Our clinical partnership with Brian will not only help to treat patients, but we are excited to gain more understanding of the complex biology of patient responses as we track these adoptively transferred CAR-engineered T-cells. This will be an important advance for Hollings, where we strive to bring cutting-edge treatment for cancer patients,” Mehrotra said. “As they say, ‘It takes a village.’ The different basic science and clinical expertises that we have developed over many years at Hollings are all coming together to implement new strategies for cancer care. It is a great testimony to a big team effort and institutional leadership and vision.”

Hess agreed and hopes the treatment will not only improve patients’ outcomes but their quality of life during treatment. “This new approach will hopefully improve the toxicity profile related to CAR-T-cell infusion as well as make the CAR-T-cells more effective in fighting the lymphoma or leukemia,” he said. “We also hope that this trial improves the availability of this dynamic therapy to patients throughout South Carolina.”

CAR T-cell Therapy

A Shot at a Cure

Patients often are referred for CAR-T-cell therapy when they have relapsed multiple times and have few or any standard therapy options left available to them. While there are associated risks, CAR-T-cell therapy provides hope to these patients.

“CAR-T-cell therapy has been able to provide durable remissions and hopefully a cure to patients who otherwise have an extremely poor prognosis,” said Hess. “FDA-approved CAR-T-cell therapy, as well as this upcoming trial, helps in the hope of offering cures to patients who otherwise would have very poor outcomes.”

Hollings first introduced CAR-T-cell therapy to South Carolina in 2019, and it is the only center in the state with both an adult and a pediatric CAR-T-cell program. In 2020, the therapy was used to treat 14 patients. In 2021, Hollings’ physicians expect to treat between 40 and 50 patients, with continued growth on the horizon, thanks to new approvals to use the therapy in additional cancer types.

Nationwide, CAR-T-cell therapy currently is being tested as a possible treatment for blood, brain, breast, gastrointestinal, lung, ovarian, pancreatic and skin cancers. On March 5, it was approved by the FDA for a common type of lymphoma called follicular lymphoma, and on March 27, it was approved for multiple myeloma.

Hess said Hollings is fortunate to have access to a clean-cell facility that is necessary to manufacture these cells and the benefit of a multidisciplinary team to oversee a program of this scope.

A patient’s journey from evaluation for CAR-T, to infusion of cells, to the post CAR-T therapy care requires multidisciplinary expertise throughout Hollings, including cellular therapy coordinators, apheresis/cryopreservation nurses, clinic nurses, nurse practitioners, pharmacists, quality coordinators, physicians, etc., all of whom specialize in cellular therapy. We also rely on the expertise of other departments outside of Hollings, such as a partnership with the emergency department and the medical intensive care unit, which help to manage side effects of CAR-T.”

By doing this work at Hollings and taking advantage of the center’s multidisciplinary team of researchers, Hess hopes to learn more about the science behind CAR-T-cell therapy to determine how to make it safer, more effective and applicable to additional cancer types, including solid tumors.

“Just like we need physicians to see patients and administer CAR-T-cell therapy, we need researchers to be able to manufacture the best possible CAR-T-cell product. They are a vital partner in making this clinical trial available to patients,” said Hess. “They’re also the team with whom we will collaborate to perform the science related to this study to advance the field and inform future studies.”

Mehrotra sees this as the beginning of an array of promising trials. Generally, most patients’ T-cells are collected and sent off to commercial labs for genetic engineering. This new in-house approach involving the creation of purer CAR-T-cells could help patients to avoid serious side effects and lower the cost of treatment, making it available for more cancer patients.

“These are exciting times for cellular therapies and engineering autologous T-cells with CARs to recognize tumor antigen puts us at the forefront of treating cancers,” said Mehrotra. “We are excited to partner with Brian and to be able to treat patients in the next six to eight months with the first in-house generated CAR-T therapy. I am sure that once we get off the ground, similar strategies can be used for targeting other cancers.”