CART22-65s Co-Administered with huCART19 in Adult Patients with Relapsed or Refractory ALL
Authors: Frey Noelle V , Gill Saar , Hwang Wei-Ting , Luger Selina M. , Martin Mary Ellen , McCurdy Shannon R. , Loren Alison W. , Pratz Keith W. , Perl Alexander E. , Barber-Rotenberg Julie , Marshall Amy , Ruella Marco , Lacey Simon F , Fraietta Joseph , Fesnak Andrew , O'brien Megan , Schanne Theresa , Brogdon Jennifer L , Engels Boris , Levine Bruce L , June Carl H , Porter David L , Hexner Elizabeth O. 
Published: November 2021

Abstract
Background: Genetically modified T cells expressing an anti-CD19 murine chimeric antigen receptor (CAR) result in response rates of up to 90% in patients with relapsed or refractory (r/r) B cell acute lymphoblastic leukemia (ALL). Durable remissions are limited by relapses of both CD19+ disease, correlating with loss of persistence, and CD19- disease, due to target antigen loss. The use of humanized CAR T products with improved persistence and dual antigen targeting are strategies that may improve relapse free survival.
Methods: Adult patients with r/r ALL were co-administered two humanized autologous CAR T cell products, one targeted to CD19 (huCART19) and the other to CD22 (CART22-65s) after fludarabine and cyclophosphamide lymphodepletion. A three day fractionated adaptive dosing scheme was used in which the second or third huCART19 and CART22-65s infusions could be held for early signs of cytokine release syndrome (CRS). Total planned dose was 2.0x10 6 CART22-65sf2 cells/kg and 2.0x10 6 huCART19 cells/kg. Safety of the novel combination was the primary endpoint of the study; feasibility and efficacy were key secondary endpoints.
Results: Of 13 treated patients (median age 46 (range 28-71)), two had received prior murine CART19 cells, 8 had prior blinatumomab, 8 had prior inotuzumab and 10 had a prior allogeneic stem cell transplant (SCT). The two products had distinct peak expansions which correlated with two clinically distinct episodes of CRS in some patients. The median time to peak huCART19 expansion was 9 days versus 16 days for CART22-65s. Eleven patients experienced CRS, all Grade 1 or 2. Two patients had immune effector cell-associated neurotoxicity syndrome (ICANS), one of which was grade 4. Two patients died within 30 days of infusion, one from complications of treatment (Grade 4 ICANS and sepsis) and one from rapidly progressive disease. One patient developed hemophagocytic lymphohistiocytosis-like syndrome that was clinically and temporally distinct from a CRS event; this was characterized by delayed pancytopenia, transaminase elevation and hypofibrinogenemia, similar to events reported in other trials of CART22. This syndrome was refractory to IL6 and IL1beta inhibition but ultimately responded to ruxolitinib.
Of the 11 patients evaluable for response, 100% achieved CR with unmeasurable residual disease (uMRD) one month after infusion. One of the 11 had molecular recurrence 9 months post infusion. The other 10 patients are alive and remain in an uMRD remission with a median follow up of 6.2 months (range 0.2 to 25 months) and none have proceeded to consolidative SCT. Three months after infusion, 9/11 patients had detectable huCART19 and 8/11 patients had detectable CART22-65s. At 6 months, 7/8 evaluable patients had detectable huCART19 cells and 4/8 patients had detectable CART22-65s. All three patients with 12 months follow-up had detectable huCART19 and CART22-65s.
Conclusion: Co-administration and adaptive dosing of CART22-65s with huCART19 in adult patients with r/r ALL is feasible and effective. The two different products demonstrated differential expansion and persistence kinetics. Despite prior exposure to CD19- and/or CD22-specific immunotherapies, all evaluable patients achieved CR with uMRD; we continue to monitor CAR T cell persistence and its impact on durability of response.

Disclosures
Frey: Novartis: Research Funding; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy; Kite Pharma: Consultancy. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Pratz: Abbvie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; Agios: Consultancy; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Perl: AbbVie: Consultancy, Research Funding; Roche: Consultancy; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Fujifilm: Research Funding; Arog: Research Funding; BMS/Celgene: Consultancy; Genentech: Consultancy; Actinium: Consultancy; Forma: Consultancy; Syndax: Consultancy; Loxo: Consultancy; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Ruella: viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties. Brogdon: Novartis Institutes for Biomedical Research: Current Employment. Engels: Novartis: Current Employment, Current equity holder in publicly-traded company. Levine: In8bio: Membership on an entity's Board of Directors or advisory committees; Ori Biotech: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Immusoft: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Other: Co-Founder and equity holder; Immuneel: Membership on an entity's Board of Directors or advisory committees; Avectas: Membership on an entity's Board of Directors or advisory committees; Akron: Membership on an entity's Board of Directors or advisory committees. June: Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company; Novartis: Patents & Royalties; AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy. Porter: American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; DeCart: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Hexner: Tmunity Therapeutics: Research Funding; Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
This trial reports outcomes from investigational products delivered as part of a clinical trial.