-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3481 KITE-753: An Autologous Rapid Manufactured Anti-CD19/CD20 CAR-T Product for the Treatment of B-Cell Malignancies

Program: Oral and Poster Abstracts
Session: 711. Cell Collection and Manufacturing of HSPCs, CAR-T Cells, and Other Cellular Therapy Products: Poster II
Hematology Disease Topics & Pathways:
Fundamental Science, Research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Jodi L Murakami*, Claudia I Guevara*, Qi Cai*, Hsing-Chuan Tsai*, Saikat Banerjee*, Da Ming Ou*, Sean C Yoder*, Sophie Viaud*, Quinn Walker*, Sunanda Kumar*, Beata Berent-Maoz*, Gunce E Cinay*, Emily Vincent*, John L Langowski* and David Barrett*

Kite, a Gilead Company, Santa Monica, CA

Background: Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have made transformative impacts on the lives of patients with B cell malignancies, relapse due to antigen escape remains a key obstacle. Hence, a Phase 1, first-in-human, open-label, multicenter study is currently ongoing to evaluate the safety and efficacy of KITE-363, a dual-targeting anti-CD19/CD20 CAR T-cell therapy, for the treatment of patients with relapsed/refractory B-cell lymphomas (NCT04989803). In conjunction with multi-antigen targeting, optimizing the CAR T-cell product attributes through next-generation manufacturing platforms provides another opportunity of improving the CAR T-cell products to enhance patient responses. In general, traditional manufacturing of CAR T-cell products involves activation, viral transduction, and ex vivo expansion for up to 15 days (Martinez-Cibrian 2022). Nonclinical studies have shown that the ex vivo expansion step in traditional manufacturing leads to more differentiated effector cells and requires a higher dose for durable in vivo responses, compared to CAR-T cells that do not undergo the expansion step (Engels 2021). The shortening of the ex vivo expansion period yields an increased proportion of juvenile (naïve and early memory) T cells in the final product, which has been linked to enhanced efficacy and improved toxicity profile (Ghassemi 2018, Dickinson 2023, Arcangeli 2022). Therefore, reducing the ex vivo expansion time will lead to an overall faster turnaround time and may also yield a higher abundance of juvenile T cells in the final product. Accordingly, KITE-753 is an autologous rapid manufactured CAR-T cell product transduced with a bicistronic lentiviral vector with resultant expression of an anti-CD19 CAR and anti-CD20 CAR.

Methods: Using a bicistronic lentiviral vector and healthy human donor T cells, we generated rapid manufactured anti-CD19/CD20 CAR-T cells (KITE-753). The bicistronic lentiviral vector encodes for an anti-CD19 CAR, containing the FMC63 binder and CD28 costimulatory domain, and anti-CD20 CAR, containing a novel CD20 binder and 41BB costimulatory domain. Anti-CD19/CD20 CAR-T cells manufactured in a more traditional process (KITE-363) served as the benchmark comparator. The final products were characterized via immunophenotyping and functionally assessed in vitro and in vivo.

Results: KITE-753 exhibited high expression of both CARs and increased proportion of juvenile T cells compared to the KITE-363 benchmark. In vitro, both CAR-T products produced cytokines, upregulated activation markers and proliferated in response to antigen-positive target cells. However, KITE-753 showed a higher frequency of activated cells and greater antigen-dependent proliferation compared to the KITE-363 benchmark. In an in vivo disseminated tumor model of B-cell acute lymphoblastic leukemia (Nalm6 tumor cell line), KITE-753 demonstrated antitumor activity at a dose more than 25-fold lower than that of the KITE-363 benchmark. Moreover, KITE-753 expansion in the peripheral blood of mice was more than 5-fold higher compared to the KITE-363 benchmark.

Conclusion: The results of these preclinical studies of KITE-753 highlight that rapid manufacturing enriches for a more juvenile, less differentiated T-cell population, resulting in superior antitumor efficacy and potency with enhanced CAR-T expansion. In addition to the potential to prevent and rescue CD19 negative relapses, the improved product potency of the rapid manufactured KITE-753 may enable the use of lower CAR-T doses in the clinic. A Phase 1, first-in-human, open-label, multicenter study is currently ongoing to evaluate the safety and efficacy of KITE-753 in patients with relapsed/refractory B-cell lymphomas (NCT04989803).

Disclosures: Murakami: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Guevara: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Astellas: Patents & Royalties. Cai: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Tsai: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Banerjee: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Ou: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Yoder: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Viaud: Calibr: Patents & Royalties; Gustave Roussy Institute: Patents & Royalties; Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Walker: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Kumar: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Berent-Maoz: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties; UCLA: Patents & Royalties. Cinay: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Vincent: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company, Patents & Royalties. Langowski: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company. Barrett: Kite, a Gilead company: Current Employment, Current equity holder in publicly-traded company.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH