FOURTH GENERATION HUCART19‐IL18 PRODUCES DURABLE RESPONSES IN LYMPHOMA PATIENTS PREVIOUSLY RELAPSED/REFRACTORY TO ANTI‐CD19 CAR T‐CELL THERAPY
نویسندگان
چکیده
Introduction: Lymphoma (NHL) patients (pts) relapsing/refractory (R/R) to anti-CD19 chimeric antigen receptor T-cells (CART) represent a challenging group in need of effective therapies. HuCART19-IL18 is 4th generation 4-1BB CART product designed express humanized CAR and secrete interleukin 18, pro-inflammatory cytokine shown enhance efficacy pre-clinical models. Its scFv may allow for better persistence, the additional use novel expedited 3-day manufacturing protocol improve product’s potency. Methods: We are conducting first-in-human trial huCART19-IL18 pts ≥18 years old with CD19+ R/R B-cell NHL or CLL, who have had at least 2 prior lines therapy including failure CART. Using modified Bayesian optimal interval dose titration design, we exploring doses between 3 300 million huCART19-IL18+ cells. The administered as single IV infusion following lymphodepleting (LD) chemotherapy. Bridging optional re-treatment permitted not achieving complete response (CR). Responses assessed 3, 6, 9, 12 months (mo) using Lugano criteria revised iwCLL CLL. Results: As March 2023, 16 enrolled. 15 manufactured all achieved minimum protocol-defined dose. 13 infused date include 5 DLBCL, 4 FL, MCL, 1 HGBCL, THRBCL pts. median age 65 (53–74), 77% male, 92% (axi-cel tisa-cel 4, brex-cel 1, tisa-cel+liso-cel 1) 67% relapsed 33% refractory number therapies was 8 (4–14); 11 (85%) received bridging therapy. LD chemotherapy used (92%) Three were treated DL1 (3 × 106 CART+ cells), DL2 (7 106), DL2-3 (2.8 107), 6 DL3 107) DL4 107). Two underwent (at DL3). Twelve evaluable safety. There no study related deaths. Most common possibly non-hematologic G3/4 toxicities included infection (17%), CRS-related hypoxia (17%) hypotension (17%). CRS seen 7 (58%) (G1 G2 2, G3 ICANS 2), which transient/reversible (25%) requiring tocilizumab. 3-month overall rate 82% (90% CI: 53–97) CR 55% 27–80). pt PR mo sustained after huCART-IL18 re-treatment. At follow-up (3–20) pts, responses durable (median reached) alive Figure 1. Correlative analyses expansion/persistence levels ongoing. research funded by: Institutional funds from University Pennsylvania Keywords: aggressive non-Hodgkin lymphoma, cellular Conflicts interests pertinent abstract J. Svoboda Consultant advisory role: Seagen, Pharmacyclics, Incyte, Genmab, BMS, Atara, Astra Zeneca, Adaptive, ADCT Research funding: TG, Merck, Adaptive D. L. Landsburg Karyopharm, Epizyme, Morphosys, Calithera, Curis, Triphase E. A. Chong Beigene, Tessa, KITE, Novartis S. K. Barta Janssen, Kyowa Kirin, Affimed, Daiichi Sankyo Honoraria: Acrotech, Seagen Nasta Roche, Gilead, Rafael, Pharmacyclics M. Ruella Employment leadership position: viTToria GSK, Bayer, NanoString, AbClon Beckman Coulter, O. Hexner Blueprint Medicines, PharmaEssentia Samus Therapeutics, Novartis, Tmunity Davis Cellares N. Frey Kite Pharmaceuticals, Sana Biotechnology, Mneumo therapeutics, Pfizer B. Levine Capstan Therapeutics Akron, Avectas, Brammer Bio, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, UTC Vycellix Porter DeCART, Bluebird Kadmon, Angiocrine, Mirror Biologics, Genentech, Jazz, Gerson Lerham, Stock ownership: Elsevier, Adecept Bio Schuster Nordic Nanovector, Loxo, AstraZeneca, Fate, Mustang BeiGene, Regeneron, MorphoSys, Legend Biotech AbbVie, DTRM, Incyte C. H. June Tmunity, Poseida AC Immune, BluesphereBio, Cabaletta, Carisma, Cellares, Alaunos, Verismo
منابع مشابه
Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T‐cell lymphoma
Peripheral T‐cell lymphoma (PTCL) is a heterogeneous group of mature, post‐thymic, T‐ and natural killer‐cell non‐Hodgkin lymphomas (NHL)— nearly all subtypes are associated with a poor prognosis. Regardless of subtype, patients with PTCL typically receive induction chemotherapy (commonly CHOP[cyclophosphamide+doxorubicin+vincristine+prednisone]) as first‐line treatment. Except for anaplastic l...
متن کاملCAR T-cell therapy in refractory large B-cell lymphoma.
Diffuse large B-cell lymphoma (DBLC) is the most common form of non-Hodgkin lymphomas. Patients with DBLC who have a relapse with chemotherapy-sensitive disease may be treated with high-dose chemotherapy followed by autologous stem-cell transplantation. However, the prognosis of patients whose diseases chemotherapy resistant, refractor to primary or salvage chemo-immunotherapy, or who have had ...
متن کاملHigh rate of complete responses to immune checkpoint inhibitors in patients with relapsed or refractory Hodgkin lymphoma previously exposed to epigenetic therapy
Options for patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) after brentuximab vedotin (Bv) and autologous stem cell transplantation (ASCT) are limited. Immune checkpoint inhibitors (ICI) are active in this population but rarely induce complete response (CR). Ten patients with R/R cHL after ASCT and Bv received pembrolizumab (n = 8) or nivolumab (n = 2). Five had been...
متن کاملPerceptual Learning in Mathematics Produces Durable Encoding Improvements
Mathematical competence requires pattern recognition for appropriate application of concepts and procedures. Research demonstrates that interventions targeting perceptual learning (PL) improve math performance. Little research, however, has directly investigated encoding changes, measured psychophysically, that may accompany PL gains in real-world tasks. We sought evidence of lasting encoding c...
متن کاملThe mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma.
Everolimus is an oral agent that targets the mammalian target of rapamycin (mTOR) pathway. This study investigated mTOR pathway activation in T-cell lymphoma (TCL) cell lines and assessed antitumor activity in patients with relapsed/refractory TCL in a phase 2 trial. The mTOR pathway was activated in all 6 TCL cell lines tested and everolimus strongly inhibited malignant T-cell proliferation wi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: Hematological Oncology
سال: 2023
ISSN: ['1099-1069', '0278-0232']
DOI: https://doi.org/10.1002/hon.3163_6