ALBERT

Description: Immunotherapy is emerging as a potent therapy for a range of hematologic malignancies including lymphomas. Indeed adoptive transfer of T cells genetically engineered to express the CD19 chimeric antigen receptor (CAR) has now received FDA approval for the treatment of patients with refractory diffuse large B cell lymphomas (DLBCL). We have developed a non-engineered T cell-based therapy to treat patients with all types of lymphomas: Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). The approach uses single T cell lines that simultaneously target a range of tumor-associated antigens (TAAs) that are frequently expressed by these tumors, including PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin. We can consistently prepare these lines by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, and adding autologous DCs as APCs that are loaded with pepmixes (15mer peptides overlapping by 11 amino-acids) spanning all 5 target antigens. The use of whole antigen should remove the HLA restriction imposed by the use of transgenic TCRs specific for single peptides, while targeting multiple antigens simultaneously would reduce the risk of tumor immune evasion. We have generated 42 clinical-grade multiTAA-specific T cell lines, comprising CD3+ T cells (mean 98±1.1%) with a mixture of CD4+ (mean 48±4.3%) and CD8+ (mean 37±4%) T cells, which expressed central and effector memory markers (CD45RO+/CD62L+/CCR7+ -- mean 14±3%; CD45RO+/CD62L+/CCR7- -- 10±2.2%; CD45RO+/CD62L-/CCR7- -- 28.3±3.6%) (n=42). The expanded lines recognized the targeted antigens PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin (range 0-463, 0-496, 0-330, 0-379 and 0-304 spot forming units (SFU)/2x105 input cells, respectively in IFNg ELIspot, n=34). None of the lines reacted against non-malignant autologous recipient cells (3±3.8% specific lysis; E:T 20:1). We have treated 33 patients: 13 with HL, 17 with aggressive NHL (diffuse large B-cell, mantle cell, or T cell lymphomas) and 3 with indolent NHLs (FL and marginal zone lymphoma). Patients received 0.5-2x107 multiTAA-T cells/m2. Of 18 patients who were infused as adjuvant therapy all but 2 remain in remission (range 3-42 months post-infusion). Fifteen patients have received multiTAA-specific T cells to treat active disease, all of whom had failed a median of 4 lines of prior therapy. Of these, 5 had transient disease stabilization followed by disease progression, 4 have ongoing stable disease, 3-18 months post-multiTAA-specific T cells while the remaining 6 (3 with HL and 3 with DLBCL) have all had complete and durable responses ( 4 to 41 months), as assessed by PET imaging. These clinical responses correlated with the detection of tumor-reactive T cells in patient peripheral blood post-infusion directed against both targeted antigens as well as non-targeted TAAs including MAGEA2B and MAGE C1, indicating induction of antigen/epitope spreading. Notably, no patient, including the complete responders, had infusion-related systemic- or neuro-toxicity. Thus, infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin has been safe and provided durable clinical benefit to patients with lymphomas. Disclosures Brenner: Marker: Equity Ownership. Heslop:Marker: Equity Ownership; Cell Medica: Research Funding; Tessa Therapeutics: Research Funding; Viracyte: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Cytosen: Membership on an entity's Board of Directors or advisory committees. Rooney:Marker: Equity Ownership. Vera:Marker: Equity Ownership. Leen:Marker: Equity Ownership.

Description: Despite an array of approved agents for the treatment of multiple myeloma (MM), most patients eventually relapse after conventional treatments. The adoptive transfer of tumor-targeted T cells has demonstrated efficacy in the treatment of patients with chemo-refractory hematological malignancies including MM. While the majority of T cell-based immunotherapeutic studies in the clinic explore genetically modified T cells that target a single tumor-expressed antigen, we have developed a strategy to generate non-engineered T cell lines that simultaneously target multiple MM-expressed antigens, thereby reducing the risk of tumor immune evasion. We manufacture multiTAA-specific T cells targeting the tumor-associated antigens PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin by culturing patient-derived PBMCs with autologous DCs loaded with pepmixes (15mer peptides overlapping by 11 aminos acids) spanning all 5 target antigens in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail. In our current clinical trial (NCT02291848), we have successfully generated multi-antigen-targeted lines from 18/ of 19 patients thus far, with one in production. The T cell lines comprise of CD3+ T cells (mean 95.6±2.2%) with a mixture of CD4+ (28.9±7.2%) and CD8+ (56.6±7.2%) T cells, which express central and effector memory markers (CD45RO+/CD62L+/CCR7+ -- 1.21±0.2%; CD45RO+/CD62L+/CCR7- -- 15.16±2.5%; CD45RO+/CD62L-/CCR7- -- 56.9±6.3%). All the expanded lines were specific for two to five target antigens with the majority of lines (13 of 18) specific for ≥3, (PRAME: Mean 45, range: 0 to 205 spot forming units (SFU)/2x105 input cells ; SSX2 mean: 57, 0 to 583, NYESO1: mean: 51, 0 to 125 , MAGE-A4 Mean: 67, 0 to 377 and Survivin mean: 53, 0 to 51), and did not react against non-malignant autologous recipient cells (2±3% specific lysis; E:T 20:1). We assessed the clonal diversity of the clinical product using TCR vβ deep sequencing analysis. We found both polyclonality and that the majority (mean 79%; range: 59 to 95%) represented rare T cell clones that were unique to the ex vivo expanded cell line and below levels of detection in the patients peripheral blood prior to infusion, thereby enabling in vivo tracking studies.. To date we have infused 18 patients with at least 2 infusions, 2 weeks apart of doses ranging from 0.5 to 2x107/m2. These patients had received a median of 4 lines of prior therapy including high dose chemotherapy with autologous stem cell rescue. Ten patients were refractory to their latest therapy and had active MM, while 8 were in remission at the time of infusion. At the 6 week evaluation period, of the 10 patients receiving multiTAA-specific T cells to treat active disease, 1 had a complete remission (CR) by the international myeloma working group (IMWG) response criteria, 1 had a partial remission (PR) and 8 others had stable disease (SD). Seven of these 10 patients were infused more than 1 year ago. Although 2 of the 7 subsequently had disease progression, the remaining 5 continue to respond, with sustained CR (1), PR (2) or SD (2). Of the 8 patients in CR at the time of T cell infusion, all remained in CR at the week 6 disease assessment and of the 6 evaluable patients who are 〉1 year post T cells, only one patient has relapsed, at 7 months after T cell infusion. These clinical responses correlated with the emergence and persistence (〉6 months) of "line-exclusive" tumor-reactive T cells in patient peripheral blood, as assessed by longitudinal tracking of infused T cell clones using TCR deep sequencing. These infused product-derived T cells were detected in both peripheral blood (mean 0.43% ±SD of 0.3 of the total repertoire) and the marrow (mean 0.61%±0.24% of total repertoire). The expansion of product-derived T cell clones was higher among patients with active MM than in patients treated in remission (active: 0.60±0.39%, remission: 0.2±0.08%, p=0.048). Notably, no patient, including the complete responder, had infusion-related systemic- or neuro-toxicity. Thus, autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin can be safely administered to patients with MM, in whom they can subsequently be detected long-term in peripheral blood and marrow, and where they produce sustained tumor responses including CR. It will be of interest to discover whether larger or more frequent doses of these T cells can produce further benefit with maintained safety. Disclosures Brenner: Marker: Equity Ownership. Heslop:Marker: Equity Ownership; Viracyte: Equity Ownership; Cell Medica: Research Funding; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Cytosen: Membership on an entity's Board of Directors or advisory committees. Vera:Marker: Equity Ownership. Leen:Marker: Equity Ownership.

Description: CD19-specific CAR-T cells are highly successful against B-cell non-Hodgkin lymphomas and acute lymphoblastic leukemia but targets for other lymphoproliferative disorders have been harder to define. Almost all HL and some NHL express the CD30 antigen both at diagnosis and relapse, and monoclonal antibodies (mAb) targeting CD30 (e.g. brentuximab) produce objective antitumor responses. However, mAb have limited bio-distribution and their benefits may be short-lived. We therefore expressed the antigen binding domain of a CD30 mAb as part of a chimeric antigen receptor (CAR) on T cells, coupled to the CD28 and z chain endodomains. We have previously published results of a phase 1 study of activated autologous CD30.CAR-T cells (CD30.CARTs) infused in patients with relapsed/refractory CD30+ HL or NHL without preceding chemotherapy (Ramos et al., J Clin Invest 2017). Of 6 patients with relapsed active HL, 1 entered complete remission (CR) that has lasted more than 3 years, and 3 had transient stable disease. No significant toxicities were observed. In order to boost the in vivo expansion and potentially the efficacy of these CD30.CARTs we are now infusing them after lymphodepleting chemotherapy (RELY-30, NCT02917083). We report here preliminary results of that study, which suggest a substantial improvement in efficacy. We have manufactured CD30.CARTs for 15 patients using retroviral transduction. Culture duration was 15±3 days, with a final transduction efficiency of 97.6%±1.8%. The cell products comprised 〉98% T cells, with a majority of them being effector T cells (CD45RO+ 95.5%±6.0%). 51Cr-release cytotoxicity assays confirmed that patients' CD30.CARTs lysed a CD30+ tumor line, HDLM-2 (45.9%±15.4% killing at a 20:1 effector:target ratio), with negligible effects on CD30− target cells (6 weeks to 〉6 months, while 2 patients had disease progression. In conclusion, our data indicate that infusion of T cells carrying a CD30.CAR containing a CD28 endodomain after lymphodepleting chemotherapy is safe, with limited toxicities at the dose levels tested. CD30.CAR expansion is improved with inclusion of pre-infusion standard lymphodepleting chemotherapy and appears to be associated with improved efficacy in relapsed patients (6/8 CR versus 1/6 CR, P = 0.03). Disclosures Rooney: Marker: Equity Ownership. Heslop:Marker: Equity Ownership; Cytosen: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Cell Medica: Research Funding; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees; Viracyte: Equity Ownership. Brenner:Marker: Equity Ownership.

Description: CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.