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EBMT 2020 Annual Meeting - New developments in the field of CAR T-cell therapy

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Tuesday 1 September, 14:30-15:30H, Auditorium 1

Various new developments in CAR-T therapy are explored in this four-part session on the final day of this year’s EBMT Online Congress. In the first, Dr. John Lin (University of Pennsylvania) discusses research on the economic value of CAR T-cell therapies.

Axicabtagene ciloleucel and tisagenlecleucel each cost $373,000 in the USA for DLBCL. Tisagenlecleucel costs $475,000 in the USA for pediatric ALL. The durable responses of CAR T-cell therapies have led to them become standard of care for these malignancies. “Although these therapies are typically covered both by insurers and national health funders in the USA and Europe, their high prices have raised questions about financial sustainability and whether their large clinical benefit is worth the high cost,” says Dr Lin.

This session will begin by explaining cost-effectiveness research, which looks at both the benefits and the costs of medical technologies in order to define their economic value. Dr. Lin will discuss why defining the cost-effectiveness of CAR T-cell therapy is so challenging and also examine what research can and cannot tell us about its economic value.

The second talk, “Safe and potent anti-CD19 CAR T-cell therapy – an experience from China”, will be presented by Dr Zhitao Ying, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies can cause severe cytokine-release syndrome (CRS) and neurotoxicity, impeding their therapeutic application. In this talk, Dr Ying will be presenting how his team generated a new anti-CD19 CAR molecule (CD19-BBz(86)) derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains. The modified CD19-BBz(86) CAR T-cells produced lower levels of cytokines, expressed higher levels of antiapoptotic molecules and proliferated more slowly than the prototype CD19-BBz CAR T-cells, although they retained potent cytolytic activity.

He will discuss the phase 1 trial of CD19-BBz(86) CAR T-cell therapy his team performed in patients with B cell lymphoma. Complete remission occurred in 6 of 11 patients (54.5%) who each received a dose of 2×108–4×108 CD19-BBz(86) CAR T-cells. Notably, no neurological toxicity or CRS (greater than grade 1) occurred in any of the 25 patients treated. CD19-BBz(86) CAR T-cells persistently proliferated and differentiated into memory cells in vivo. He concludes: “Thus, therapy with the new CD19-BBz(86) CAR T-cells produces a potent and durable anti-lymphoma response without causing neurotoxicity or severe CRS, representing a safe and potent anti-CD19 CAR T-cell therapy.”

CAR T-cell technologies and strategies for solid cancer will then be discussed in the third presentation by Dr Hinrich Abken, Regensburg Center for Interventional Immunology and University Hospital Regensburg, Regensburg, Germany. He will discuss that, even though therapy with chimeric antigen receptor (CAR) redirected T cells has achieved spectacular remissions of refractory leukemia/lymphoma, the treatment of solid tumours so far remains challenging.

He will discuss recent developments in which CAR T-cells are used as “living factories” to deposit immune modulating cytokines in the targeted tumour tissue aiming at converting the immune cell environment into a more favourable one to sustain a productive anti-tumour response.

Such TRUCKs (T cells redirected for unrestricted cytokine release and killing) releasing IL-12 or IL-18 upon CAR engagement of antigen in the CAR targeted tumour lesion are superior in attracting and activating the innate immune response in the tumour lesion. “The strategy thereby combines CAR mediated tumour targeting with the delivery of a transgenic protein ‘on demand’ in order to modulate the T cell anti-tumour response and to induce an innate cell response,” says Dr Abken.

The final talk, “future of CAR T-cell therapies: toward allogeneic CAR T-cells”, will be presented by Professor Stéphane Depil, MD, PhD, Cancer Research Center of Lyon, Centre Léon Bérard, and Université Claude Bernard Lyon 1, France.

He will discuss that, while CAR T-cell therapy represents a major breakthrough in the field of immuno-oncology, some issues exist with autologous CAR T-cells. “These include time for manufacturing and the need for interim therapies in progressing patients, wide variations in terms of quality and quantity of T-cells, and the difficulty of obtaining enough cells for re-dosing,” says Professor Depil.

“Off-the-shelf” allogeneic CAR T-cells pre-manufactured from third-party donors may provide solutions to these different problems. However, allogeneic T-cells possess foreign immunological identities that can lead to graft-versus-host disease (GvHD) and rejection of allogeneic cells. Use of non-αβ T-cells, virus-specific memory T-cells or TCR gene-editing technologies can be used to mitigate the risk of GvHD. Furthermore, several approaches may limit the elimination of the allogeneic cells, including the use of HLA-typed T-cells, the optimisation of the lymphodepletion protocol, and the disruption of MHC molecules on the surface of allogeneic CAR T-cells, optionally combined with expression of NK cell inhibitors to make these cells invisible to the host immune system.

“Several clinical trials are ongoing with allogeneic CAR T-cells in hematologic malignancies,” concludes Professor Depil. “The development of next-generation allogeneic CAR T-cells represents an active area of research; improved allogeneic CAR T-cell products will pave the way for further breakthroughs in cancer treatment.”