This article reports the outcomes of a clinical trial of CD28-containing CD19-specific chimeric antigen receptor (CAR) T cells in pediatric, adolescent, and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Minimal disease burden at entry and use of high-dose cyclophosphamide conditioning are reported to be associated with more favorable outcomes.

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

Background: While doublet therapies provide important first-line treatment options in metastatic renal cell carcinoma (mRCC), novel and mechanistically distinct agents are needed for pts who are not cured by/intolerant of such therapies. Due to the high incidence (~80%) of CD70 antigen expression in primary and mRCC, yet limited expression in normal tissue, ccRCC is an attractive proof-of-concept tumor for CD70 directed allogeneic CAR T. TRAVERSE (NCT04696731), a first-in-human trial, seeks to identify a maximum tolerated dose (MTD) of ALLO-316 after conditioning with fludarabine/cyclophosphamide with/without ALLO-647 in pts with advanced or metastatic ccRCC. ALLO-316 is an anti-CD70 allogeneic CAR T cell product that utilizes TALEN® gene editing to knock out TCRα constant gene to reduce the risk of graft-versus-host disease (GvHD) and knock out CD52 gene to permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells without affecting allogeneic CAR T cells. Methods: This multicenter, single-arm, open-label, 3+3 dose-escalation trial enrolls adults with advanced or metastatic ccRCC and ≥1 measurable lesion and ECOG Performance Status 0 or 1. Prior treatment with an immune checkpoint inhibitor and a vascular endothelial growth-factor targeted therapy was required, with evidence of progression on/after treatment or discontinuation due to toxicity. ALLO-316 is administered at escalating doses (40 - 240 × 106 allogeneic CAR+ cells IV) on Day 0 after conditioning. The primary endpoint is a target incidence rate for dose-limiting toxicities (DLTs) <33% in the first 28 days after infusion of ALLO-316. Results: By 12/3/2022, 18 pts with ccRCC (median age: 63 yrs; 82% male) were enrolled; all (100%) 17 pts who received ALLO-316, had metastatic disease with 3 lines (median) of prior therapy. Eleven (65%) of these pts experienced CRS, all low Gr except one (6%) Gr 3. No ICANS or GVHD was observed. One (6%) DLT (elevated LFT) was observed and required dose expansion. MTD has not yet been reached. Three pts achieved best overall response of PR at all time points with two PRs confirmed at subsequent visits; ORR = 12% and disease control rate (DCR) = 71%. In pts with confirmed CD70+ tumors (n=9), confirmed ORR = 22% (unconfirmed ORR = 33%) and DCR = 100%. High CAR T cell expansion was observed in peripheral blood (median Cmax > 35,000 copies/μg) and high VCN in available tumor aspirates (n=3). Conclusions: ALLO-316, an allogeneic CAR T cell product targeting CD70 in advanced mRCC, is demonstrating encouraging antitumor activity and a manageable safety profile. A single administration of ALLO-316 could be an effective treatment for pts with CD70+ solid tumors, including RCC, and hematologic malignancies. The MTD for ALLO-316 in TRAVERSE will support Phase 2 trial design. Enrollment of pts with CD70+ tumors is ongoing. Citation Format: Samer Srour, Ritesh Kotecha, Brendan Curti, Jad Chahoud, Alexandra Drakaki, Lily Tang, Lovely Goyal, Sacha Prashad, Victoria Szenes, Kevin Norwood, Sumanta Pal. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT011.

Background: Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder (EBV-LPD) complicating allogeneic hematopoietic cell transplant (alloHCT) most frequently present as malignant, high grade, diffuse large B cell lymphomas (DLBCL) that do not respond to reduction in immune suppression. Rituximab induces remissions in approximately 55% of those with radiographically demonstrable disease. Median survival reported for rituximab-refractory EBV-LPD patients (pts) ranges from 16 - 56 days. There are few other treatment options. EBV-cytotoxic T lymphocytes (CTLs) offer a possible treatment approach. We evaluated the efficacy and safety of EBV-CTLs have been evaluated in 2 clinical trials in alloHCT recipients with EBV+ disease. Methods: As part of 2 ongoing clinical trials (95-024 and 11-130) 57 pts received EBV-CTLs derived from unrelated third-party donors (13 on 95-024 and 18 on 11-130) or primary stem cell donors (26 on 95-024). Fifty-one pts were treated for monomorphic DLBCL, 3 polymorphic, 1 NK/T cell lymphoma and 2 for viremia alone. Subjects on 11-130 (n = 18) had a median age of 52y, 8 were male, all had failed prior rituximab. Pts on 95-024 (n = 39) had a median age of 21y, 23 were male, and 28 had failed prior rituximab. Subjects in both studies received up to 5 cycles of EBV-CTL infusions; each cycle consisting of 1 or 2×106 cells/kg weekly for 3 weeks. Results: Of the 18 recipients of 3rd party EBV-CTLs on 11-130, 9 pts had complete response (CR), 3 had partial response (PR) and 1 had stable disease (SD) for a response rate of 67% and non-progression rate of 72%. The median duration of CR+PR was 318d. Kaplan-Meier (KM) overall survival (OS) was 71.8% at 1 and 2y. KM progression-free survival was 66.7% at 1y. Of 39 pts on 95-024, 23 had CR, 1 PR, and 3 had SD, for a response rate of 62% and non-progression rate of 69%. Strikingly, the 1y OS for rituximab-refractory pts in both studies was 50% and 49% for pts treated with 3rd party and transplant donor-derived EBV-CTLs, respectively. Four patients on 11-130 and 6 patients on 95-024 died within 2 months of the first EBV-CTL infusion due to progression of EBVLPD (N = 6), leukemic relapse (N = 2), or other causes (N = 2); no death was considered related to treatment. EBV-CTLs had low toxicity: no pts developed cytokine release syndrome or GvHD requiring systemic therapy. Conclusions: EBV-CTLs produce high response rates that are durable; pts who achieved CR had no relapses of EBV LPD. The OS in both studies far exceeded the survival reported for this patient population. EBV-CTLs had a favorable safety profile and were well tolerated. Citation Format: Susan E. Prockop, Ekaterina Doubrovina, Karim Baroudy, Farid Boulad, Ramzi Khalaf, Esperanza B. Papadopoulos, Craig Sauter, Victoria Szenes, Stephanie Suser, Gloria Wasilewski, Julianna Ruggierio, Richard J. O'Reilly. Epstein-Barr virus-specific cytotoxic T lymphocytes for treatment of rituximab-refractory Epstein-Barr virus-associated lymphoproliferative disorder. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT107. doi:10.1158/1538-7445.AM2015-CT107

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