> Details
Garfall, Alfred L.;
Cohen, Adam D.;
Lacey, Simon F;
Tian, Lifeng;
Hwang, Wei-Ting;
Vogl, Dan T.;
Waxman, Adam;
Lancaster, Eric;
Nelson, Anne Marie;
Ferthio, Regina;
Fesnak, Andrew;
Lamontagne, Anne;
Brennan, Andrea;
Guilliams, Jamie;
Gladney, Whitney Lynn;
Melenhorst, J. Joseph;
Young, Regina M;
Siegel, Don L.;
Levine, Bruce L;
Brogdon, Jennifer;
Isaacs, Randi E.;
June, Carl H;
Milone, Michael C.;
Stadtmauer, Edward A.
Combination Anti-Bcma and Anti-CD19 CAR T Cells As Consolidation of Response to Prior Therapy in Multiple Myeloma
Sharing
Reference
management
Direct link
Bookmarks
Remove from
bookmarks
Share this by email
Share this on Twitter
Share this on Facebook
Share this on Whatsapp
- Media type: E-Article
- Title: Combination Anti-Bcma and Anti-CD19 CAR T Cells As Consolidation of Response to Prior Therapy in Multiple Myeloma
- Contributor: Garfall, Alfred L.; Cohen, Adam D.; Lacey, Simon F; Tian, Lifeng; Hwang, Wei-Ting; Vogl, Dan T.; Waxman, Adam; Lancaster, Eric; Nelson, Anne Marie; Ferthio, Regina; Fesnak, Andrew; Lamontagne, Anne; Brennan, Andrea; Guilliams, Jamie; Gladney, Whitney Lynn; Melenhorst, J. Joseph; Young, Regina M; Siegel, Don L.; Levine, Bruce L; Brogdon, Jennifer; Isaacs, Randi E.; June, Carl H; Milone, Michael C.; Stadtmauer, Edward A.
- imprint: American Society of Hematology, 2019
- Published in: Blood
- Language: English
- DOI: 10.1182/blood-2019-131515
- ISSN: 0006-4971; 1528-0020
- Origination:
- Footnote:
- Description: <jats:p>BACKGROUND: Anti-BCMA CAR T cells are effective in relapsed/refractory multiple myeloma (RRMM), but most patients eventually progress. Extensive prior therapy and high disease burden in RRMM pts may compromise CAR T cell safety, feasibility, and efficacy, and rare BCMA-neg/CD19+ MM cells with enhanced clonogenic potential may mediate relapse after anti-BCMA CARs. We therefore initiated a trial of anti-BCMA CAR T cells (CART-BCMA) as consolidation of response to prior MM therapy, including high-risk (HR) pts responding to first-line therapy, and combined CART-BCMA with anti-CD19 CAR T cells (CTL119). Both CART-BCMA and CTL119 are 4-1BB/CD3z-based CARs transduced via lentiviral vector. CART-BCMA was previously reported (Cohen et al JCI 2019) and exhibited 64% response rate at 5x108 cell dose following cyclophosphamide (cy) alone as lymphodepleting chemo in RRMM. CTL119 is a humanized version of tisagenlecleucel.</jats:p> <jats:p>METHODS: To assess safety/feasibility of CART-BCMA + CTL119, Phase A (PhA) is evaluating the combination in pts responding (≥MR) to ≥3rd line therapy (or ≥2nd line if exposed to all major agents). After early PhA results showed no excessive toxicity, Phase B (PhB) began enrolling HR pts (R-ISS 3, complex karyotype, PC leukemia, or <PR or early progression on imid/PI induction) responding to first- or second-line therapy, <1y from diagnosis, and unexposed to cytotoxic chemo (except low-dose cy). PhB patients are randomized to receive CART-BCMA +/- CTL119. Both products are dosed at 5x108 CAR+ cells in 3 divided doses (10%, 30%, 60%) after cy 300 mg/m2 + fludarabine 30 mg/m2 daily x 3d (cy/flu). Pts receive maintenance (maint) lenalidomide or pomalidomide beginning d30 or upon recovery from toxicity. Here we report initial results of 6 PhA and 4 PhB pts.</jats:p> <jats:p>RESULTS: 6/7 enrolled PhA pts were infused; 1 pt died due to CNS progression before infusion. 4/4 enrolled PhB pts were infused (2 CART-BCMA alone, 2 CART-BCMA + CTL119). See table for age & prior # therapies; 9/10 had HR cytogenetics or were R-ISS 3. Regarding mfg feasibility, 2 PhA pts (05, 07) failed to meet full target doses; all 4 PhB pts achieved full dose. Two subjects (01, 03) had the 3rd (60%) dose held due to early fevers. CRS was gr 0-2 by ASTCT criteria and was observed in pts with both high and low disease burden (table). No neurologic toxicity was observed. Gr 3-4 toxicities were mainly hematologic; 3/6 PhA pts had either ANC <1000 and plt <50K at day 30, whereas 4/4 PhB pts recovered ANC & plts by day 30. Aside from CRS, serious AEs ≥possibly related to CAR T cells included pneumonia, sepsis-associated AKI, CMV, pancreatitis, and bone pain, all occurring in PhA pts. Among patients with IMWG-measurable disease, ≥PR was observed in 5/5 PhA pts, including 1 pt with VGPR despite only 10% CART-BCMA dose (pt 05), and 3/3 PhB pts. Responses are ongoing in 2/6 PhA and 3/4 PhB patients (table). Initiation of maint was feasible in 4/6 PhA (median start d67) and 4/4 PhB (median start d48) pts; no recurrence of CRS was observed with maint initiation. All pts exhibited in vivo expansion of both CART19 and CART-BCMA, including those with low disease burden; no re-expansion was observed with maint initiation. Among 5 patients with ongoing responses at day 90 who were evaluable for MRD by flow cytometry, 4 had MRD with detectable BCMA expression (dim in 2 pts, bright in 1 pt, variable in 1 pt), and 1 was MRD-negative (sensitivity ~10-5); 4/5 exhibited absence of normal plasma cells, suggesting possible ongoing anti-BCMA immune surveillance but resistance of residual MM PCs. Among 8 patients who received both CART-BCMA and CTL119 in either PhA or PhB, 5 had ongoing absence of circulating B cells at last follow-up, including two pts with ongoing responses at 1y and 4m, providing evidence for long-term CAR T cell activity in MM patients.</jats:p> <jats:p>CONCLUSIONS: Preliminary results support safety and high initial response-rate of CART-BCMA + CTL119 after cy/flu in MM. In pts with low disease burden responding to prior therapy, including first-line therapy, CAR T cells expanded in vivo and generated clinical responses with low-grade CRS and no neurotoxicity. Preliminarily, hematologic toxicity and feasibility of maint seem more favorable in first-line setting. Addition of CTL119 did not clearly prevent progression after CART-BCMA in the PhA population (3-9 prior lines); data from PhB with randomization +/- CTL119 are immature. Accrual is ongoing, and updated results will be presented at the meeting.</jats:p> <jats:p>Table.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Garfall: Surface Oncology: Consultancy; Novartis: Patents & Royalties: inventor on patents related to tisagenlecleucel (CTL019) and CART-BCMA, Research Funding; Janssen: Research Funding; Amgen: Research Funding; Tmunity: Honoraria, Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding. Lacey:Novartis: Research Funding; Tmunity: Research Funding; Novartis: Patents & Royalties: Patents related to CAR T cell biomarkers. Tian:Novartis: Research Funding. Hwang:Novartis: Research Funding; Tmunity: Research Funding. Vogl:Active Biotech: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Lancaster:novartis: Research Funding. Nelson:Novartis: Research Funding. Ferthio:Novartis: Research Funding. Fesnak:Novartis: Research Funding. Melenhorst:National Institutes of Health: Research Funding; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Incyte: Research Funding; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding, Speakers Bureau; Stand Up to Cancer: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Genentech: Speakers Bureau. Young:novartis: Research Funding. Levine:Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Vycellix: Membership on an entity's Board of Directors or advisory committees; Incysus: Membership on an entity's Board of Directors or advisory committees; Cure Genetics: Consultancy; Novartis: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership; CRC Oncology: Consultancy; Avectas: Membership on an entity's Board of Directors or advisory committees. Brogdon:Novartis: Employment. Isaacs:Novartis: Employment. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Milone:Novartis: Patents & Royalties, Research Funding. Stadtmauer:Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy.</jats:p> </jats:sec>
- Access State: Open Access