Unrelenting progress: Blood cancer research and treatment at Penn Medicine

Driven by their passion to cure cancer, Penn researchers leverage their deep understanding of genetics and the human immune system to blaze a new path in personalized cell and gene therapies. Penn Medicine researchers are evolving new approaches to advance the personalized cell and gene therapies, and have developed Penn-grown approaches, including the creation, manufacturing, and distribution of chimeric antigen receptor T-cell therapy. They have also introduced innovative treatments created elsewhere, often based on early discoveries at Penn, and often with input from Penn clinician-scientists.

Pushing the CART

Writing in Molecular Therapy in 2009, Drs. Carl June and Michael Milone reported that primary human T cells subjected to lentiviral gene transfer resulted in significant expansion, yielding large numbers of T cells with >85% CAR expression. In an immunodeficient mouse xenograft model of primary human pre-B-cell acute lymphoblastic leukemia, human T cells expressing anti-CD19 CARs containing CD137 (4-1BB) exhibited the greatest antileukemic efficacy and prolonged (>6 months) survival in vivo, and were significantly more effective than cells expressing CARs containing TCR-zeta alone or CD28-zeta signaling receptors. This was among the first pivotal preclinical studies to demonstrate the enhanced in vivo efficacy of CD19-targeted CAR T cells by incorporating the 4-1BB signaling domain.

Obe-cel: First CAR T-cell therapy for adult ALL to be FDA-approved without a Risk Evaluation and Mitigation Strategies (REMS) program

Obecabtagene autoleucel (obe-cel) is the third CAR T-cell immunotherapy to be FDA-approved for treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults, but the first to do so without a required REMS program. The Abramson Cancer Center is an authorized treatment center for obe-cel.

The object of REMS programs is to ensure that unique severe risks and toxicities of CAR T therapy, not mitigated by the labeling alone, are recognized and managed to ensure the safe use of CAR T. These risks include cytokine release syndrome and neurotoxicity syndromes.

The required REMS add logistical burdens and other impediments to the production and dissemination of CAR T therapy, creating access barriers for many patients. Thus, in June 2023, the American Society for Transplantation and Cellular Therapy (ASTCT) 80/20 Subcommittee, of which Noelle Frey, MD, MSCE, of Penn Hematology-Oncology was a contributing member, reconsidered REMS programs. It was the strong consensus of the subcommittee that safety and quality workflows embedded in existing resources within the cellular therapy field would allow for the elimination or significant reduction and simplification of current CAR-T REMS programs. Obe-cel was the first CAR T introduced without a formal REMS program, and in June 2025, the remaining approved CAR T therapies were exempted, as well.

The FDA approval of obe-cel occurred on the basis of a single-arm trial that included patients with relapsed or refractory B-cell ALL. At a median follow-up of 20.3 months, 77% of patients responded, with complete remission in 55%. The median duration of response was 14.1 months.

Liso-cel^® first CAR-T for marginal zone lymphoma

Approved by the U.S. Food and Drug Administration in December 2025, lisocabtagene maraleucel (liso-cel) is the first agent for the treatment of relapsed or refractory marginal zone lymphoma (MZL). Liso-cel was previously approved by the FDA for the treatment of relapsed or refractory large B-cell lymphoma and relapsed or refractory small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL).

A rare, indolent non-Hodgkin lymphoma, MZL arises from chronic inflammation in the marginal zones of the spleen, lymph nodes, tonsils, and other secondary lymphoid tissues. Because these tissues filter and target pathogens and foreign antigens, they play a crucial role in both cell-mediated and humoral immunity. Of the three types of MZL, the most common is mucosa-associated lymphoid tissue (MALT) lymphoma.

Liso-cel is an autologous CD19-directed chimeric antigen receptor T-cell therapy, and as such is a descendant of tisogenlecleucel (tisa-cel), created at Penn Medicine, which targets the same protein.

The efficacy of liso-cel was evaluated in the MZL Cohort of TRANSCEND FL (NCT04245839), an open-label, multicenter, single-arm trial in adults with relapsed or refractory follicular lymphoma or MZL who had received two or more lines of systemic therapy or who relapsed after hematopoietic stem cell transplant. The trial included patients with an ECOG performance of 0 or 1.

In this study, the overall response rate in the intention-to-treat population was 84.4% and the complete response rate in this population was 55.8%. The median duration of response was not reached.

Stephen Schuster, MD, is the principal investigator at the Abramson Cancer Center for the TRANSCEND-CLL-004 clinical study of liso-cel in adult subjects with relapsed or refractory CLL or small lymphocytic lymphoma (SLL). Dr. Schuster and David Porter, MD, are co-authors of a recent retrospective study evaluating the safety, efficacy, and resource utilization of liso-cel in the standard-of-care setting for relapsed/refractory large B-cell lymphoma.

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.