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Abstract

Abstract: S286

Type: Oral Presentation

Session title: CART cells

Background

Immunotherapy using patient-derived CAR-T cells has achieved complete remission and durable response in highly refractory populations. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T-cell availability.

Aims
We designed a phase I trial in pediatric and adult B-cell ALL (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) by using non-viral donor-derived CD19 CAR-T cells generated by electroporation of Sleeping Beauty (SB) transposon plasmids and differentiated according to Cytokine Induced Killer (CIK) cell protocol. 

Methods

The clinical trial follows a four-dose escalation scheme (1x106, 3x106, 7.5x106 and 15x106 transduced CAR+ T cells/kg) using the novel Bayesian Optimal Interval Design (BOIN).

Results

The cellular product was produced starting from 50 ml of donor-derived peripheral blood and consisted of mostly CD3+ lymphocytes with 43.05%±3.56% CAR expression. Eighteen out of 19 productions were released and cell manufacturing at target dose levels was succeeded in all patients. Four pediatric and 9 adult patients were infused with a single dose of CAR-T cells (n=3 HLA identical sibling, n=4 MUD, n=6 haploidentical donor). The leukemic burden in the bone marrow (BM) post lymphodepletion/pre-infusion ranged from 0% to 98%. CARCIK-CD19 were well tolerated and the maximum tolerated dose was not found. Toxicities reported were two grade I and a grade II cytokine release syndrome (CRS), with absence of graft-versus-host disease (GvHD), neurotoxicity, and dose-limiting toxicities in any of the treated patients. Six out of 7 patients, receiving the highest doses, achieved CR and CRi at day 28. Five out of 6 patients in CR were also minimal residual disease (MRD)-negative, while one was MRD+ and relapsed at day +49. Robust expansion was achieved in the majority of the patients as defined by detectable CAR-T cell detection in peripheral blood (PB). CAR-T cells were measurable by transgene copy PCR up to 7 months with a mean persistence of 97.6 ± 17.57 days (follow up ranging from 28 days to 1 year). The vector integration sites of the patients’ PB and the cell products reflected the classical random distribution of SB without any tendency for gene dense regions.

Conclusion

Our data demonstrate that SB-engineered CARCIK-CD19 cells are able to expand and persist in pediatric and adult B-ALL patients relapsed after HSCT, with important implications for allogeneic manufacturing and non-viral technology.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Allogeneic, B cell acute lymphoblastic leukemia, CAR-T, CD19

Abstract: S286

Type: Oral Presentation

Session title: CART cells

Background

Immunotherapy using patient-derived CAR-T cells has achieved complete remission and durable response in highly refractory populations. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T-cell availability.

Aims
We designed a phase I trial in pediatric and adult B-cell ALL (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) by using non-viral donor-derived CD19 CAR-T cells generated by electroporation of Sleeping Beauty (SB) transposon plasmids and differentiated according to Cytokine Induced Killer (CIK) cell protocol. 

Methods

The clinical trial follows a four-dose escalation scheme (1x106, 3x106, 7.5x106 and 15x106 transduced CAR+ T cells/kg) using the novel Bayesian Optimal Interval Design (BOIN).

Results

The cellular product was produced starting from 50 ml of donor-derived peripheral blood and consisted of mostly CD3+ lymphocytes with 43.05%±3.56% CAR expression. Eighteen out of 19 productions were released and cell manufacturing at target dose levels was succeeded in all patients. Four pediatric and 9 adult patients were infused with a single dose of CAR-T cells (n=3 HLA identical sibling, n=4 MUD, n=6 haploidentical donor). The leukemic burden in the bone marrow (BM) post lymphodepletion/pre-infusion ranged from 0% to 98%. CARCIK-CD19 were well tolerated and the maximum tolerated dose was not found. Toxicities reported were two grade I and a grade II cytokine release syndrome (CRS), with absence of graft-versus-host disease (GvHD), neurotoxicity, and dose-limiting toxicities in any of the treated patients. Six out of 7 patients, receiving the highest doses, achieved CR and CRi at day 28. Five out of 6 patients in CR were also minimal residual disease (MRD)-negative, while one was MRD+ and relapsed at day +49. Robust expansion was achieved in the majority of the patients as defined by detectable CAR-T cell detection in peripheral blood (PB). CAR-T cells were measurable by transgene copy PCR up to 7 months with a mean persistence of 97.6 ± 17.57 days (follow up ranging from 28 days to 1 year). The vector integration sites of the patients’ PB and the cell products reflected the classical random distribution of SB without any tendency for gene dense regions.

Conclusion

Our data demonstrate that SB-engineered CARCIK-CD19 cells are able to expand and persist in pediatric and adult B-ALL patients relapsed after HSCT, with important implications for allogeneic manufacturing and non-viral technology.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Allogeneic, B cell acute lymphoblastic leukemia, CAR-T, CD19

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