Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease. Patients with different molecular and immunophenotypic profiles can receive the same CD19 CAR-T product and still end up with very different outcomes. Clinicians already track MYC, TP53 and cell-of-origin. A newer, easy-to-overlook aggressive subtype is CD5-positive DLBCL — and until recently, no study had specifically asked whether CD5 expression blunts CAR-T results. A new real-world cohort from Nagoya University is the first to answer that question, and the findings carry a sharp clinical warning.

What Is CD5-Positive DLBCL?

CD5 is normally a T-cell surface marker, but a minority of B-cell lymphomas also express it on tumor cells.

  • Among de novo DLBCL, CD5 positivity is only 5–10%, mostly the non-GCB subtype, frequently with MYC/BCL2 co-expression, a higher IPI score, and aggressive behavior.
  • Even with a DA-EPOCH-R plus high-dose methotrexate regimen, roughly 30% still progress to relapsed/refractory (r/r) disease.
  • CD5 can activate the ERK pathway and induce IL-10 secretion, helping build an immunosuppressive microenvironment — a mechanism thought to drive immune resistance.

Prior CAR-T prognostic research focused on MYC, CAR-product T-cell exhaustion and the inflammatory tumor microenvironment. Whether tumor CD5 expression itself affected CAR-T had simply been unclear.

The Study Population

The study enrolled 106 r/r DLBCL patients who received commercial CD19 CAR-T (axi-cel / liso-cel / tisa-cel) at Nagoya University between 2021 and 2024.

  • Screening flow: 126 underwent leukapheresis; 11 had other lymphomas and 9 never received the infusion (manufacturing failure, clinical deterioration), leaving 106 analyzed.
  • Grouping by the most recent biopsy (IHC / flow): CD5-positive 26 (25%), CD5-negative 76 (72%), with 4 unevaluable.

A telling imbalance

The CD5-positive rate in the CAR-T cohort was 25% — far above the 5–10% seen in de novo DLBCL. That gap suggests CD5-positive DLBCL is more likely to become relapsed/refractory and to ultimately reach the CAR-T step.

Lymphodepletion was uniformly FluCy (fludarabine/cyclophosphamide; the center does not use bendamustine for conditioning), and bridging therapy included various salvage chemotherapies, bispecific antibodies and radiotherapy.

Core Clinical Results (median follow-up 12 months)

1. Response rates

  • CD5-positive: CR 42%, ORR 54%
  • CD5-negative: CR 55%, ORR 74%

The objective response rate was numerically worse in the CD5-positive group, though the difference did not reach statistical significance.

⚠ The critical subgroup: Among patients who were already in progressive disease (PD) before infusion, the CD5-positive group had 6 cases — all progressed after CAR-T, with zero complete responses. By contrast, of 26 CD5-negative patients who were in PD before infusion, 27% (7/26) still achieved a complete response. The practical takeaway: for a CD5-positive DLBCL patient who is already progressing at the time of CAR-T infusion, CD19 CAR-T alone is very unlikely to control the disease — alternative plans should be readied in advance.

2. Survival

  • CD5-positive: median PFS 5.0 months, median OS 16 months
  • CD5-negative: median PFS 20 months, median OS not reached

PFS comparison P=0.004; OS P=0.072. Cumulative incidence of progression: 3-month 39% vs 20%; 12-month 55% vs 34% (P=0.015). After multivariable Cox regression adjusting for confounders, CD5 positivity was an independent adverse prognostic factor for both PFS (HR=2.39, P=0.006) and OS (HR=2.78, P=0.013).

3. Notable subgroup findings

  • Line of therapy matters. At second-line CAR-T the gap between CD5-positive and negative was relatively small; by third-line and beyond the adverse effect of CD5 was markedly amplified — suggesting earlier use of CAR-T may partly offset CD5-driven resistance.
  • CD5 positivity predicted worse outcomes regardless of GCB or non-GCB cell-of-origin.
  • Sample sizes across individual CAR-T products were too small to rank them.

4. Safety: toxicity was no different

There was no statistically significant difference between CD5-positive and negative groups in any-grade or grade 3–4 CRS or ICANS, nor in tocilizumab or corticosteroid use. CD5 does not appear to change CAR-T-related immune toxicity — the outcome gap comes from intrinsic tumor resistance, not from differing toxicity.

5. After CAR-T failure

Progression after CAR-T occurred in 58% of CD5-positive versus 36% of CD5-negative patients. Post-progression options included chemotherapy, the bispecific antibody epcoritamab, radiotherapy and best supportive care. In a small sample, bispecific-antibody therapy looked better than chemotherapy, but the numbers are limited. Once CD5-positive disease fails CAR-T, the overall prognosis is poor.

Limitations

  • Single-center, retrospective study with inherent selection bias; external multi-center validation is needed.
  • CD5 testing came from referring hospitals with non-uniform IHC interpretation; CD5 status can even convert between biopsies.
  • Only 26 CD5-positive cases, and median follow-up was just 12 months — long-term outcomes are immature.
  • CAR-T product T-cell subsets and exhaustion markers were not measured, so the exact molecular mechanism of CD5-mediated resistance remains unresolved.

Clinical Takeaways

  • CD5 positivity is an independent adverse prognostic marker for r/r DLBCL treated with CD19 CAR-T (worse PFS and OS) — while CRS/ICANS risk is comparable.
  • Key warning: CD5-positive DLBCL that is already progressing at infusion is rarely controlled by CD19 CAR-T alone;备选 (backup) strategies should be planned ahead.
  • CD5-positive patients do relatively better with earlier (second-line) CAR-T; delaying to later lines magnifies the adverse effect — this subtype should not be deferred.
  • CD5-positive DLBCL is a high-risk CAR-T subgroup that will likely need combination strategies and novel-target cell therapies to improve outcomes.
Note: This article summarizes a peer-reviewed study for educational purposes and is not medical advice. Treatment decisions must be made with a qualified specialist and a multidisciplinary team.

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Source: adapted from a literature explainer by 小淋说CAR-T (published October 26, 2026), summarizing Kawaguchi T, Shimada K, Furukawa K, et al. Impact of CD5 expression on outcomes for chimeric antigen receptor-T cell therapy in relapsed and refractory diffuse large B-cell lymphoma. Cytotherapy. 2026;28:102015. DOI:10.1016/j.jcyt.2025.102015.