ALPHA Study: ALLO-501 Produced Deep and Durable Responses in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma Comparable to Autologous CAR T

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 >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.

Long-term follow-up for the development of subsequent malignancies in patients treated with genetically modified IECs

“…Additionally, gene-editing strategies including CRISPR-Cas9 and transcription activator-like effector nucleases have been used to modify CAR T cells to reduce the risk of graft-versus-host disease or rejection. 47 Transcription activator-like effector nuclease disruption of the TRAC gene and the CD52 locus was recently associated with a chromosomal abnormality on chromosome 14, the location of the TRAC gene, but in a region associated with myeloproliferative disorders. Although there was clonal expansion of the modified cells, no progression to malignancy has occurred to date.…”

The role of CAR-T cell therapy as second line in diffuse large B-cell lymphoma

“…Multiple ongoing trials, including ALPHA (NCT03939026) and ALPHA2 (NCT04416984), use genetically modified anti-CD19 allogenic CAR products using TALEN gene editing and have reported promising results in early phase trials. 47 , 48 Other ongoing early trials include the anti-CD19 UCART019 (NCT03166878) and the CTX130 anti-CD70 allogeneic CRISPR-Cas9 (NCT04502446). 49 , 50 We look forward to seeing the results of the next wave of CAR-T trials currently under evaluation.…”

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma

“…In particular, treatment with PBCAR0191, an anti-CD19 CAR-T product in which endogenous TCR is disrupted by gene editing to prevent GvHD, together with an intensified lymphodepletion, has shown clinical benefit in the majority of NHL patients, yielding high rates of overall and complete response with promising activity in both CD19 CAR naïve subjects and those who progressed following auto-CD19 CAR therapy ( 56 , 57 ). Other ongoing studies are testing ALLO-501/ALLO-501A, alternative allogeneic anti-CD19 CAR-T products modified by gene editing to disrupt the T-cell receptor alpha constant gene and the CD52 gene, respectively to reduce the risk of GvHD and allow the use of anti-CD52 mAb to delay host T cell reconstitution and graft rejection, have provided encouraging results ( 58 , 59 ).…”