Modulation of both tumor and T cell apoptosis to enhance CART immunotherapy

Chimeric Antigen Receptor T-cell (CART) immunotherapy has led to unprecedented responses in patients with refractory or relapsed B-cell Non-Hodgkin’s Lymphoma (NHL). However, only one-third of patients achieve long-term remission. We hypothesized that enhanced sensitivity to apoptosis in tumor cells would increase the efficacy of CART therapy. We demonstrated that low expression in leukemic blasts of pro-apoptotic factors related to the extrinsic pathway are associated with poor outcomes after treatment with CART19 in both pediatric and adult B-ALL. In another recently published study, we studied the role of the intrinsic pathway and, in particular, BCL-2 in NHL patients treated with CART19. We observed that the response rate in patients harboring BCL-2 translocation and gain was the most inferior overall as compared to that in patients without BCL-2 alterations.

Based on these results, we combined pro-apoptotic small molecules with CART in vitro and in vivo. While observing initial synergy, we noticed toxicity with long-term CART treatment. To combat this, we developed a strategy to endow CART cells with resistance to pro-apoptotic drugs and developed this combination in multiple models. Finally, we studied the role of BCL-2 in CART cells and found that CART cells overexpressing BCL-2 as measured by NanoString® nCounter® gene expression analysis persist longer in vivo and lead to better tumor control compared to wild-type CART. In conclusion, our work highlights the importance of apoptosis in both cancer cells and CART cells in driving response to CART immunotherapy and describes potential strategies to overcome resistance.

• CART cell immunotherapy is leading to outstanding clinical results in lymphoma, but only one-third of patients have long-term responses
• Resistance to apoptosis in cancer cells is a key feature of CART immunotherapy failure, and strategies to enhance tumor apoptosis during CART therapy lead to better tumor control
• Apoptosis also plays a role in the function of CART cells, limiting their role term function; modulation

Marco Ruella, M.D.

Assistant Professor of Medicine, Scientific Director, Lymphoma Program, Division of Hematology and Oncology and Center for Cellular Immunotherapies, University of Pennsylvania

Dr. Marco Ruella obtained his medical degree with high honors and completed his specialization in clinical hematology at the University of Torino, Italy. He was attending physician at the Hematology and Cell Therapy Division of the Mauriziano Hospital and was an Instructor at the Biotechnology School at the University of Torino. From late 2012, he was a Post-doctoral Fellow, and then an Instructor at the University of Pennsylvania in the Center for Cellular immunotherapies (Drs. June and Gill). From 2017 to 2018 he served as Associate Director of Dr. June’s laboratory. In 2018, Dr. Ruella was appointed Assistant Professor of Medicine in the Division of Hematology/Oncology and the Center for Cellular Immunotherapies and Scientific Director of the Lymphoma Program at the Hospital of the University of Pennsylvania. Dr. Ruella was awarded many awards and honors, including the inaugural SITC EMD-Serono Cancer Immunotherapy Clinical Fellowship (2014), the AACR-BMS Oncology Fellowship in Clinical Cancer Research (2015), the ASH Scholar Award (2016), a NIH K99-R00 award (2017), the “Paola Campese” Award Leukemia Research (2017), the Cancer Support Community Award (2018), the 2018 ASH Joanne Levy, MD, Memorial Award for Outstanding Achievement, the Gilead Sciences Research Scholar in Hematology/Oncology and the Gabrielle’s Angel Foundation Award (2020), the Leukemia and Lymphoma Society, Translational Research Program (2021), and the Alan Steinrberg Award (2022). Dr. Ruella is the author of numerous peer-reviewed publications on targeted immunotherapies for hematological cancers and is an inventor in several patents on CART therapy and the Scientific Founder of viTToria biotherapeutics.