Next-generation “armored” car T-cell therapy shows promising results for lymphoma patients

Next-generation “armored” CAR T-cell therapy showed promising results in small studies of patients whose B-cell lymphoma continued to resist multiple other rounds, including commercial CAR T-cell therapy. The new treatment reduced cancer in 81% of patients, causing complete remission in 52%, and some treated patients experienced a durable remission for more than two years. The findings, led by researchers at the University of Pennsylvania's Perelman School of Medicine, today New England Journal of Medicine.

CAR T-cell therapy – Individualized forms of cancer Immunotherapy His team in Carl Jone, Maryland and Penjas were first successfully developed and revolutionised the treatment of many blood cancers. Over 50% of lymphoma patients receiving currently available CAR T-cell therapy do not experience long-term remission. Of the seven FDA-approved CAR T-cell therapy products, four are used to treat various types of B-cell lymphoma. Unfortunately, for those who have had cancer return or become resistant after CAR T-cell therapy, the prognosis is insufficient and there are few options. Previous studies have shown that retreating these patients with existing CAR T-cell therapies does not work well.

“We are excited that this new generation of CAR T-cell therapy created here with Pen was extremely effective in patients who have already tried everything available to treat lymphoma,” said Jakub Svoboda, an associate professor of hematology oncology who led clinical trials at Penn Medicine's Abramson Cancer Center. “It also encourages us to see that the toxicity of this new product is no different from what we already see in commercial vehicles.”

The addition of IL18 did not raise new or unexpected safety concerns beyond known side effects of CAR T-cell therapy, such as cytokine release syndrome (CRS) and neurotoxicity. Researchers also found that the types of patients with previously administered CAR T-cell therapy could potentially collisions Effectiveness of hucart19-il18.

New strategies add cytokines to make Car T cells more effective

Twenty-one patients in this Phase I clinical trial had the median value of seven other treatments prior to enrolling in this study, but all but one had already tried CAR T-cell therapy approved for the cancer type. Despite these aggressive treatments, as cancer continues to progress, it is due to immunosuppression and T-cell fatigue that reduce the effectiveness of anti-cancer therapy.

To combat these challenges, the vague professor of Richard W. Immunotherapy, a team led in June, developed a new “armored” car T-cell product called the Hucart19-IL18. Like most other CAR T-cell products in lymphoma, it targets a surface antigen called CD19. However, this version has been further modified to secrete interleukin-18 (IL18), a proinflammatory cytokine that can strengthen the immune system. T cells. In doing so, it further promotes its ability to protect car T cells and attack cancer cells, June explained.

This study represents the important development in the ongoing evolution of CAR T cell therapy, as cytokine-enhanced CAR T was first tested in patients with hematological cancer. By analyzing blood samples from patients after treatment, the researchers found strong evidence that adding IL18 to CAR T cells contributed to robust response rates.

Based on these results, we believe that incorporating cytokine secretion into CAR T-cell design has broad implications for strengthening cell therapy, even beyond hematological cancer. With longer T-cell persistence and expansion, this strategy could be potent in settings where car T is not similarly running, such as solid tumors. ”

Carl Jeune, Maryland

Production of HUCART19-IL18 also uses a process developed by Penn's Cell Immunotherapy Center, reducing the production time of Car T cells to just three days. For patients with aggressive, rapidly growing cancer, this means that automotive T-cell therapy can be started faster than is currently possible in 9-14 days of standard manufacturing time. Previous studies suggest that shorter manufacturing times may improve T-cell efficacy.

I'll continue my research

The researchers are planning several other clinical trials, including studies extending HuCART19-IL18 to patients with acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Another study of non-Hodgkin's lymphoma using similar IL18 armored CAR T-cell products is currently enrolling patients. On the manufacturing side, the team is partnering with a pen spin-out company to improve the process of how these automotive T cells are created and re-penetrating into patients.

“Thanks to the teamwork between courageous patients and the science and clinical teams, we know that bringing this type of new treatment from the lab bench to the patient's bedside is only possible in places like Penmedicine,” Suboboda said. “The biopsy and cytokine data from this study provide a wealth of information on patients who recur after CAR T cell therapy, which will help researchers better understand the science of recurrence of CAR T cell therapy in general.”

This study was made possible with institutional funding from the University of Pennsylvania. Svoboda previously reported preliminary results data from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting and the 2024 European Hematology Association (EHA) Parliament.