Novel platform shows preclinical and early clinical promise in accelerating the production of more effective CAR-T cell therapy

Investigators of the Vall d’Hebron Institute of Oncology’s (VHIO) Experimental Hematology Group have co-developed a novel platform to manufacture CAR-T cell therapy more rapidly and effectively which could reduce the production turnaround time for patients with relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL) to receive personalized immunotherapy.

Published in Cancer Discovery* the investigators, led by corresponding author Michael J. Dickinson, Lead of the Aggressive Lymphoma Disease Group at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Australia, report findings in preclinical models and preliminary data from an ongoing first-in-human study of YTB323, a novel, autologous CD19-directed CAR-T cell therapy manufactured using T-Charge™, in patients with r/r DLBCL, a type of non-Hodgkin lymphoma (NHL).

CAR-T – chimeric antigen receptor T-cell – therapy is a type of immunotherapy specifically developed for each individual patient and involves genetically reprogramming the patient’s own immune system cells to express specific chimeric antigen receptors (CAR) on the cell surface, which are then reinfused to the patient to target and attack tumor cells.

“CAR-T cell therapies directed against CD19 have demonstrated unprecedented efficacy in patients with different B-cell malignancies. However, traditional CAR-T cell manufacturing requires a lengthy culturing process including ex-vivo T-cell expansion, leading to a door-to-door time of around 20-25 days. For patients with particularly aggressive tumors, this is simply too long to wait,” says Pere Barba, a Lead Investigator of VHIO’s Experimental Hematology Group, Director of the Advanced Therapies Program at the Vall d’Hebron University Hospital (Vall d’Hebron Barcelona Hospital Campus), and a co-author of this present study*.

“We have developed the T-charge™ next generation platform that does not require this expansion phase and thus reduces the manufacturing time of the final product to under two days. In addition, since the CAR-T cells are not exposed to cytokines for so long they are less exhausted and more effective,” adds Barba.

With this novel platform, the turnaround of personalized CAR-T cell therapy—from the time of extracting the patient’s own immune cells to the return of the finished product at the hospital where the treatment is to be administered—could ultimately achieve a median door-to-door time of 10 days.

In preclinical mouse models, the investigators observed that the novel YTB323 CD19-directed CAR-T therapy manufactured using the T-charge™ platform achieved superior antitumoral activity at a lower dose versus traditionally processed CAR-T cell therapy. Based on these preclinical findings, a first-in-human phase I study was initiated at the Vall d’Hebron University Hospital in a cohort of patients with relapsed/refractory non-Hodgkin lymphoma (diffuse large B cell lymphoma and B-cell acute lymphoblastic leukemia).

“Interim results in patients with diffuse large B cell lymphoma are encouraging. We have observed that treatment with T-charge-processed CAR-T cells, at doses 25 times lower than CAR-T therapy approved for these tumors, showed a promising overall safety profile and a response rate of between 75 and 80%. The preservation of T-cell stemness in the product also translates into promising early clinical activity with a desirable safety profile,” concludes Pere Barba.Updated results of this clinical trial were presented by Pere Barba as an oral presentation at the 2022 American Society of Hematology (ASH) Annual Meeting, December 10-13, New Orleans, Louisiana.

Innovative research in advanced therapies

Over recent years, VHIO has consolidated its strong commitment to investigating advanced therapies, leading to significant advances in the field of Immuno-oncology and advanced therapeutics through its Comprehensive Cancer Immunotherapy and Immunology Institutional Program (CAIMI and CAIMI II) funded by the BBVA Foundation, as well as the Spanish Association Against Cancer’s (AECC) Excellence Program – Advanced Therapies Accelerator Program to develop new gene and cellular therapy products and improve existing ones in our pipeline. This fifth VHIO Institutional Program launched in 2023.

Reference:

*Dickinson MJ, Barba P, Jager U, Shah NN, Blaise D, Briones J, Shune L, Boissel N, Bondanza A, Mariconti L, Marchal AL, Quinn DS, Yang J, Price A, Sohoni A, Treanor LM, Orlando EJ, Mataraza J, Davis J, Lu D, Zhu X, Engels B, Moutouh-de Parseval L, Brogdon JL, Moschetta M, Flinn IW. A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-Cell Stemness Shows Enhanced CAR T-Cell Efficacy in Preclinical and Early Clinical Development. Cancer Discov. 2023 May 30:CD-22-1276. doi: 10.1158/2159-8290.CD-22-1276. Epub ahead of print. PMID: 37249512.