ALPHA Study: ALLO-501 Produced Deep and Durable Responses in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma Comparable to Autologous CAR T
Authors: Neelapu Sattva S. , Nath Rajneesh , Munoz Javier , Tees Michael , Miklos David B. , Frank Matthew J. , Malik Shahbaz A. , Stevens Don , Shin Chu Ri , Balakumaran Arun , Loomis-Navale Lynn , Goyal Lovely , Nguyen Anh , Locke Frederick L. 
Published: November 2021

Abstract
Background
Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-501 is a genetically modified anti-CD19 AlloCAR T™ cell product that uses TALEN ® gene editing to disrupt the T-cell receptor alpha constant gene and the CD52 gene with TALEN to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647 (anti-CD52 monoclonal antibody [mAb]), for selective and transitory host lymphodepletion (LD). Here we present updated safety and efficacy data including consolidation cohort. ALLO-501 uses Cellectis technologies.
Methods
ALPHA (NCT03939026) is a Phase 1, open-label, multicenter dose escalation study in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) or follicular lymphoma (FL) and ≥2 prior lines of therapy (including an anti-CD20 mAb). Pts with donor specific antibodies and baseline rituximab &gt;15 ng/mL were excluded. Following LD with ALLO-647 (39, 60, or 90 mg), fludarabine 30 mg/m 2/d x 3d (F), and cyclophosphamide 300 or 500 mg/m 2/d x 3d (C), escalating doses of ALLO-501 (40, 120, or 360 x 10 6 viable CAR T cells [DL1, DL2 and DL3]) were given. For pts receiving one ALLO-501 dose, retreatment was allowed. In the consolidation cohort, pts with ≥stable disease (SD) at D28 receive consolidation therapy with second ALLO-647 dose of 30 mg and ALLO-501 (DL2) cell infusion.
Results
As of July 9, 2021, 98% (46/47) of pts enrolled were treated (1pt excluded due to renal failure) with ALLO-501 in the single dose cohort (n=39) and consolidation cohort (n=7). Median time from enrollment to LD was 5 days. Pts had advanced-stage disease (Stage III: 17 [37.0%], Stage IV: 26 [56.5%]) and were heavily pretreated (median of 4 prior lines [range 2-12]). In the study, 20% of pts were R/R after prior Auto CAR T therapy; 54% were chemo refractory.
No dose-limiting toxicities (DLTs) or GvHD observed. No pts experienced Grade (Gr) 2+ immune effector cell-associated neurotoxicity syndrome (ICANS). Gr 1/2 cytokine release syndrome (CRS) occurred in 21.7% (10/46) and Gr 3+ in 1 pt with a single dose and was managed with standard guidelines. Cytopenias were the most common adverse event (AE) and occurred in 82.6% of pts. Gr 3+ infections occurred in 23.9% of pts. As previously reported, 5 pts died after treatment, 4 of non-treatment related AEs and 1 of Aspergillus pneumonia (263d post CAR T) deemed related to ALLO-501.
Efficacy in Auto CAR T naïve pts (n=36) was evaluated in the modified-intent-to-treat (mITT) population and was nearly identical to the intent-to-treat (ITT) population. The objective response (ORR) and complete response (CR) rates were 75% and 50%, respectively. Among pts with LBCL (n=13), ORR and CR were 61.5% (95% CI: 31.6, 86.1) and 46.2% (95% CI: 19.2, 74.9). In FL (n=23), the ORR was 82.6% (95% CI: 61.2, 95.1) and CR was 52.2% (95% CI: 30.6, 73.2). Of 7 pts in consolidation cohort, 5 FL pts received consolidation and 2 LBCL pts received 1 st CAR T dose and are awaiting consolidation. Of the 4 pts (all FL) that had a tumor assessment after consolidation dose (D56), ORR and CR were 100% and 75%, respectively.
Among the 18 FL and 11 LBCL Auto CAR naïve pts who had the opportunity to be followed for 6 months, 27.8% of FL and 36.4% of LBCL pts remained in CR at month 6. The longest ongoing CR is 15+ months. All consolidation pts dosed remain in response with the longest response being a CR at month 4.
Conclusions
This updated data continues to highlight that allogeneic CAR T therapy can be safely and effectively delivered to pts with R/R NHL with encouraging durability of response. Ninety-eight percent of pts enrolled were treated with ALLO-501 with a median of 5 days from enrollment to therapy, supporting the ease and speed pts were able to be treated with AlloCAR T therapy. The safety was manageable with no DLT or GvHD; no Gr 2+ ICANS and limited CRS. Infection rates were similar to that observed in autologous CAR T trials. The 6-month CR rate of 36.4% in LBCL is similar to the 6-month CR rates reported in the pivotal trials of autologous CAR T therapies(NEJM 2017;377:2531-2544. Lancet 2020;396(10254):817. NEJM 2019;380:45-56). Consolidation dosing demonstrated similar safety and improved efficacy vs single dosing with ORR of 100% and CR of 75% in pts who had tumor evaluation after consolidation.

Disclosures
Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Munoz: Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Miklos: Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Pharmacyclics: Patents & Royalties. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Shin: Allogene Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Loomis-Navale: Allogene: Current Employment, Current equity holder in publicly-traded company. Nguyen: Allogene: Current Employment; Nektar: Ended employment in the past 24 months. Locke: Wugen: Consultancy, Other; EcoR1: Consultancy; Umoja: Consultancy, Other; Cowen: Consultancy; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Emerging Therapy Solutions: Consultancy; Janssen: Consultancy, Other: Scientific Advisory Role; Legend Biotech: Consultancy, Other; Gerson Lehrman Group: Consultancy; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding.

OffLabel Disclosure:
Discussion of fludarabine and cyclophosphamide in combination with ALLO-647 as conditioning regimen prior to administration of ALLO-501 in NHL patients.