Introduction: Evidence Points to CAR-T

Before CAR-T cell therapy existed, patients with chemotherapy-refractory diffuse large B-cell lymphoma had a median overall survival of 6.3 months, a complete response rate of 7%, and only 20% alive at two years. That was the landscape SCHOLAR-1 described in 2017, and it is the baseline against which every subsequent development in this space should be measured.

CAR-T has fundamentally changed that calculus. The pivotal trials established response rates of 73 to 83%, complete response rates of 53 to 58%, and a meaningful fraction of patients who appear to be in durable long-term remission, potentially cured after a single infusion. Beyond whether or not CAR-T works, the challenge in 2026 is identifying the right patients, understanding who can benefit from transplant versus CAR-T, and knowing what is coming next for the patients who still relapse.

The Original Trials: Establishing the Foundation

Axi-cel (ZUMA-1): In 101 treated patients, 64% had three or more prior lines of therapy, 77% were refractory to second-line or subsequent therapy, and 30% were primary refractory. The overall response rate was 83% with 58% complete responses. Grade 3 to 4 CRS occurred in 11% and grade 3 to 4 ICANS in 30%, the neurotoxicity rates that made the early CAR-T experience demanding and drove a decade of engineering work to improve the safety profile.

Liso-cel (TRANSCEND): In 270 patients with a median of three prior lines, 67% chemorefractory, the overall response rate was 73% and complete response rate was 53%. Grade 3 to 4 CRS was only 2% and grade 3 to 4 ICANS only 10%, a dramatically better safety profile than axi-cel that expanded the range of patients who could be treated.

These trials defined the initial third-line and beyond indication for CAR-T and established that durable complete responses were achievable in patients who historically had no good options.

CAR-T Versus Auto-Transplant: The Second-Line Question

Three randomized trials compared CD19 CAR-T versus standard second-line chemotherapy followed by autologous stem cell transplant in patients with early relapse or primary induction failure: ZUMA-7 (axi-cel), TRANSFORM (liso-cel), and BELINDA (tisa-cel).

ZUMA-7 and TRANSFORM both showed event-free survival benefits for CAR-T versus standard care. At a median follow-up of 47 months, ZUMA-7 showed a three-year overall survival of 56% versus 48% in favor of axi-cel, an OS benefit that materialized with longer follow-up. TRANSFORM showed a trend toward OS benefit with liso-cel. BELINDA was negative, primarily due to logistical and study design issues that impaired treatment delivery.

The critical nuance, well established from ZUMA-7 and TRANSFORM, is that approximately 74 to 75% of enrolled patients were primary induction failures who never responded to first-line therapy. The SOC arm was structurally disadvantaged from the start because approximately half the patients receiving salvage chemotherapy never became chemosensitive, experiencing an event immediately. The trials were designed to get second-line approval, and they succeeded, but not to answer the specific question of whether chemosensitive early-relapse patients do better with CAR-T or transplant.

What the data do clearly support: for primary induction failure and for patients who are not chemosensitive to salvage therapy, CAR-T is the preferred approach. For chemosensitive patients with early relapse, the case for CAR-T remains strong, though the "two shots on goal" argument (cure with auto, then CAR-T if needed) remains valid.

CAR-T in transplant-ineligible patients: A pilot study evaluated liso-cel specifically in patients who were not eligible for autologous transplant due to age, organ function, or comorbidities. Median age 74, ECOG 0/1/2 in 31%/43%/26% of patients. Overall response rate close to 80%, complete response rate close to 60%, excellent 18-month PFS and OS. No new safety signals with longer follow-up. This supports using CAR-T directly, rather than declining to treat, in patients who cannot tolerate auto-HCT.

Practical Approach: CAR-T or Auto?

For patients under 75, primary induction failure or relapse within 12 months: CAR-T is the preferred second-line approach per NCCN and the major trials.

For patients under 75, relapse beyond 12 months: Standard second-line salvage chemotherapy, and if chemosensitive, autologous transplant is appropriate. CAR-T remains an option, particularly if there are concerns about transplant eligibility.

For patients over 75, or those with comorbidities that preclude transplant: CAR-T is more accessible than auto: no mobilization, no high-dose chemotherapy, manageable toxicity in selected patients. The lymphodepleting regimen of fludarabine and cyclophosphamide is well tolerated even in patients with intermediate organ function.

Post-CAR-T relapse: Bispecific antibodies (glofitamab, epcoritamab) are the primary option. In selected younger patients who achieve a CR with salvage therapy post-CAR-T, allogeneic transplant may offer a chance at cure. We have performed more allogeneic transplants for lymphoma at our center in the last two years than in the prior decade, particularly for patients who relapse after CAR-T.

Next-Generation CAR-T: What Is in Development

The limitations of current CAR-T are well known: a median PFS of under seven months in third-line and beyond settings, with only 40% of complete responders remaining in remission at six to twelve months. The field is pursuing multiple engineering strategies to improve on these outcomes.

KITE-753 (dual CD19/CD20 CAR-T with rapid manufacturing): Uses the same bicistronic construct as axi-cel but targets both CD19 and CD20, with CD28 co-stimulation for one receptor and 4-1BB co-stimulation for the other. The rapid manufacturing process preserves a higher proportion of naïve and early memory T cells, cells with greater functional fitness. At dose level 3 in 19 patients: 79% complete response rate, no grade 3 to 4 CRS, no grade 3 to 4 ICANS. Pivotal trials are planned for 2026 in third-line and beyond DLBCL, and a phase 3 randomized trial comparing KITE-753 versus axi-cel in second-line DLBCL is planned.

Ronde-cel (CD19/CD20 CAR-T, CD62L-enriched): Manufactured from CD62L-enriched T cells, selectively capturing naïve and central memory cells with superior persistence and expansion potential. Vein-to-site time of 16 days. Peak CAR-T expansion at least three times higher than currently approved products. In 60 patients in third-line and beyond DLBCL: 93% overall response rate, 76% complete response rate, and among CR patients who reached six months of follow-up, 100% are still in complete response. No grade 3 to 4 CRS; grade 3 to 4 ICANS only 4% after prophylactic dexamethasone was added. The PiNACLE trial is expanding the phase 1/2 cohort, and PiNACL-H2H is a phase 3 randomized trial (N=400) of Ronde-cel versus standard of care (axi-cel or liso-cel).

Cema-cel (allogeneic anti-CD19 CAR-T, off-the-shelf): The ALPHA3 trial is evaluating cema-cel in a novel MRD-guided design: patients who complete first-line R-CHOP or PolaRCHP are tested for MRD using Foresight Clarity MRD; those who are MRD-positive at end of therapy despite being in clinical remission are randomized to observation versus cema-cel. This addresses patients in remission with measurable residual disease before clinical relapse. No currently approved product exists for this setting.

Trials Available Now

For patients with relapsed DLBCL who are interested in clinical trials, several options are currently enrolling or open:

  • LYOL: Phase 3 of liso-cel in relapsed large B-cell lymphoma

  • KITE-753: Phase 1/2 expansion in third-line DLBCL; phase 3 versus axi-cel in second-line planned

  • Ronde-cel PiNACL-H2H: Phase 3 versus axi-cel or liso-cel in third-line and beyond

  • ALPHA3: MRD-guided allo CAR-T in MRD-positive first remission

For Patients

If you have been diagnosed with large B-cell lymphoma that has returned or did not respond to treatment, CAR-T cell therapy is a powerful option that uses your own immune cells, reprogrammed to recognize and destroy lymphoma cells, and then infused back into your body. In patients whose lymphoma returned quickly or never responded to the first treatment, CAR-T is now the preferred second-line approach, not something to hold in reserve.

The manufacturing process takes approximately six weeks, so timing matters. If your oncologist suspects your lymphoma may have come back, ask about CAR-T referral early, before the disease has a chance to progress further or your overall health declines.

For older patients or those with other medical conditions: age alone is not a barrier to CAR-T. The lymphodepletion chemotherapy used before CAR-T infusion is much gentler than autologous transplant conditioning, and we regularly treat patients into their eighties with good outcomes in carefully selected cases. Ask for a referral to a CAR-T center for evaluation.

Key Takeaways

  • SCHOLAR-1 established the historical baseline: 7% CR rate, 6.3-month median OS in chemorefractory DLBCL. CAR-T has transformed these outcomes.

  • Axi-cel (ZUMA-1): 83% ORR, 58% CR; liso-cel (TRANSCEND): 73% ORR, 53% CR, with substantially lower CRS/ICANS rates.

  • ZUMA-7 and TRANSFORM: CAR-T superior to standard second-line therapy plus auto-HCT in primary induction failure and early relapse; three-year OS benefit confirmed in ZUMA-7 (56% vs 48%).

  • Liso-cel is feasible and effective in transplant-ineligible patients (older, intermediate organ function, ECOG 0–2); no new safety signals with follow-up.

  • KITE-753 (dual CD19/CD20, rapid manufacturing): 79% CR at dose level 3, no grade 3–4 CRS or ICANS; phase 3 trials planned for 2026.

  • Ronde-cel (CD62L-enriched, dual CD19/CD20): 93% ORR, 76% CR, 100% of CR patients in ongoing remission at six months; phase 3 versus axi-cel/liso-cel enrolling.

  • ALPHA3: MRD-guided allo CAR-T in MRD-positive first remission; addresses high-risk patients before clinical relapse.

  • Refer early; plan bridging; consider allo-HCT for younger patients relapsing post-CAR-T who achieve a subsequent remission.

References

  1. Crump M, et al. SCHOLAR-1: outcomes in refractory DLBCL. Blood, 2017.

  2. Neelapu S, et al. ZUMA-1: axi-cel in R/R DLBCL. New England Journal of Medicine, 2017; five-year update Blood, 2023.

  3. Abramson J, et al. TRANSCEND: liso-cel in R/R LBCL. Lancet, 2020; update Blood, 2024.

  4. Westin J, et al. ZUMA-7: axi-cel vs standard second-line therapy. New England Journal of Medicine, 2023.

  5. Kamdar M, et al. TRANSFORM: liso-cel vs standard second-line therapy. Presented at ASCO 2024.

  6. Pilot study. Liso-cel in transplant-ineligible R/R NHL. Lancet Oncology, 2022.

  7. Dahiya S, et al. KITE-753 (dual CD19/CD20 CAR-T). ASH 2025. Abstract 265.

  8. Larson S, et al. Ronde-cel in R/R DLBCL. ASH 2025. Abstract 668.

  9. Shaughnessy P. "CAR-T Therapy for Relapsed Aggressive Lymphomas." Presented at the 2026 Best of Hematology, Austin, TX, May 2026.