The early Drosophila embryo is a large syncytial cell that compartmentalizes mitotic spindles with furrows. Before furrow ingression, an Arp2/3 actin cap forms above each nucleus and is encircled by actomyosin. We investigated how these networks transform a flat cortex into a honeycomb-like compartmental array. The growing caps circularize and ingress upon meeting their actomyosin borders, which become the furrow base. Genetic perturbations indicate that the caps physically displace their borders and, reciprocally, that the borders resist and circularize their caps. These interactions create an actomyosin cortex arrayed with circular caps. The Rac-GEF Sponge, Rac-GTP, Arp3, and actin coat the caps as a growing material that can drive cortical bending for initial furrow ingression. Additionally, laser ablations indicate that actomyosin contraction squeezes the cytoplasm, producing counterforces that swell the caps. Thus, Arp2/3 caps form clearances of the actomyosin cortex and control buckling and swelling of these clearances for metaphase compartmentalization.

Background In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL). Methods Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor. Results The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56–3.49] and 1.21 [0.56–2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44–1.49] and 0.95 [0.58–1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01–0.07] and 0.08 [0.01–0.67], respectively) and study-specific neurological events (0.16 [0.08–0.33] and 0.05 [0.02–0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor. Conclusions After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL. Trial registration: NCT02631044 and NCT02348216

Background There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel). Methods Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET. Results Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes. Conclusions Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel. Clinical trial registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Introduction: Chimeric antigen receptor T cell therapies have shown encouraging, durable responses in patients with R/R LBCL, yet no head-to-head clinical trials comparing options exist to date. We conducted 2 separate pair-wise MAICs to compare treatment effects of liso-cel vs both axi-cel and tisagenlecleucel. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel (TRANSCEND NHL 001 [TRANSCEND]; NCT02631044; N = 256) vs axi-cel (ZUMA-1; NCT02348216; N = 101) and vs tisagenlecleucel (JULIET; NCT02445248; N = 111). Outcomes of interest included efficacy (overall and complete response rates [ORR/CRR], overall survival [OS], and progression-free survival [PFS]) and safety (cytokine release syndrome [CRS] by Lee criteria, neurological events [NEs], aphasia, encephalopathy, infections, hypogammaglobulinemia, and prolonged cytopenia). Individual patient data (IPD) from TRANSCEND were adjusted to match the marginal distribution (eg, mean, variance) of clinical factors among patients from ZUMA-1 and JULIET. Patients from TRANSCEND were removed from the IPD set if they did not satisfy eligibility criteria specified in the comparator trial for each MAIC. IPD for patients who remained in the TRANSCEND data set were weighted using a method-of-moments propensity score model. Baseline characteristic and outcome definitions were aligned with those in ZUMA-1 or JULIET. Clinically relevant prognostic factors (identified from literature, TRANSCEND data, and 5 independent clinical experts) were adjusted collectively in a stepwise fashion by ranked order. Key matched and adjusted variables in 1 or both comparisons included: disease histology, Eastern Cooperative Oncology Group performance status (ECOG PS), central nervous system (CNS) involvement, prior allogeneic/autologous hematopoietic stem cell transplant (HSCT), tumor burden, International Prognostic Index score, response to last therapy, bulky disease, and age. Efficacy outcomes in patients without bridging therapy were evaluated; however, ZUMA-1 and TRANSCEND treatment protocols differed in bridging therapy use (not allowed in ZUMA-1) and time to product availability (median, 17 vs 24 days, respectively). Results : After aligning definitions of baseline characteristics among trials, substantial differences were noted for ECOG PS of 2, tumor burden, active CNS involvement, number of prior lines of therapy, prior allogeneic HSCT, and history of hematologic comorbidities between studies. Overall, TRANSCEND included a larger sample size and broader patient population vs comparator trials, allowing for successful MAIC adjustments. When comparing TRANSCEND to ZUMA-1, MAIC-weighted efficacy outcomes were comparable between trials: odds ratios (ORs [95% CI]) for ORR and CRR with liso-cel vs axi-cel were 0.85 (0.48-1.52) and 0.78 (0.47-1.27), respectively; hazard ratios (HRs [95% CI]) for OS and PFS were 1.15 (0.80-1.65) and 1.30 (0.96-1.77), respectively (Figure). When limited to patients without bridging therapy, differences between trials remained statistically insignificant. MAIC-weighted safety outcomes showed a favorable safety profile for liso-cel, with a statistically significant lower odds of CRS, NEs (including aphasia and encephalopathy), and infections vs axi-cel. ORs (95% CI) for all-grade and grade ≥3 CRS with liso-cel vs axi-cel were 0.06 (0.03-0.13) and 0.16 (0.06-0.47), respectively; ORs for all-grade and grade ≥3 NEs were 0.21 (0.13-0.35) and 0.31 (0.18-0.54), respectively. When comparing TRANSCEND to JULIET, liso-cel showed a statistically significant higher ORR/CRR and longer OS/PFS than tisagenlecleucel. ORs (95% CI) for ORR and CRR achieved with liso-cel vs tisagenlecleucel were 2.78 (1.63-4.74) and 2.01 (1.22-3.30), respectively; HRs (95% CI) for OS and PFS were 0.67 (0.47-0.95) and 0.65 (0.47-0.91), respectively. Adjusted safety outcomes showed generally comparable profiles with lower ORs (95% CI) for all-grade and grade ≥3 CRS with liso-cel vs tisagenlecleucel: 0.53 (0.32-0.89) and 0.10 (0.03-0.31), respectively. Conclusions : MAIC-weighted outcomes suggest that liso-cel may provide a more well-balanced overall efficacy and safety profile for the treatment of R/R LBCL, with better efficacy compared with tisagenlecleucel and better safety compared with axi-cel. Disclosures Maloney: A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Bioline Rx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding. Kuruvilla:Bristol-Myers Squibb Company: Consultancy; AbbVie: Consultancy; Antengene: Honoraria; TG Therapeutics: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding. Fox:AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; Atarabio: Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria; Jansen: Honoraria. Li:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bonner:Eversana: Current Employment. Zhang:Eversana: Current Employment. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

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