---
title: "Naive-like T cell proportion predicts durable response to axi-cel in lymphoma"
id: "nature-1-determinants-of-response-to-car-t-cell-therapy-in-a-multicenter-multi-trial"
canonical_url: "https://medichelpline.com/clinical-feed/nature-1-determinants-of-response-to-car-t-cell-therapy-in-a-multicenter-multi-trial"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Nature Medicine"
source_url: "https://www.nature.com/articles/s41591-026-04707-w"
published_at: "2026-10-23T09:52:10.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Naive-like T cell proportion predicts durable response to axi-cel in lymphoma
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/nature-1-determinants-of-response-to-car-t-cell-therapy-in-a-multicenter-multi-trial
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Nature Medicine
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41591-026-04707-w)
- **Published At:** 2026-10-23T09:52:10.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The investigators analyzed **axicabtagene ciloleucel (axi-cel)** products from 580 patients with non-Hodgkin lymphoma across multiple clinical trials, with median follow-up of 41.9 months. - A high proportion of **naive-like (CCR7+CD45RA+) T cells** in the infusion product was the single strongest feature associated with prolonged progression-free survival (PFS; hazard ratio = 0.46, 95% CI: 0.31–0.68, P = 9.8 × 10−5, high versus low naive-like groups). - The study team observed no impact of the naive-like proportion on safety outcomes in the reported dataset. - Tumor microenvironment characteristics were assessed in a subset of 112 patients; the relationship between naive-like cells and efficacy remained independent of those microenvironment features. - Multivariate models placed the naive-like phenotype ahead of clinicopathologic features (for example, inflammatory markers and tumor burden) and it remained significant after adjusting for product expansion. - An inverse correlation appeared between prior lines of therapy and the proportion of naive-like T cells in both infusion products and matched apheresis samples, suggesting earlier treatment may preserve these cells. - Key observations were validated in an independent cohort of 203 patients treated with axi-cel–based therapy or brexucabtagene autoleucel. - Mass cytometry (CyTOF) in a subgroup of 116 products confirmed that a **CD8 naive-like** phenotype lacking exhaustion markers (TIGIT, LAG-3, PD-1) associated with improved PFS. - The authors note that knowledge of product characteristics and long-term benefit remains fragmentary and that systemic inflammatory markers have limited causal interpretability when evaluated alone. - The source did not report specific manufacturing protocols, dosing regimens, or detailed trial-by-trial methodology in the text provided here; those details are not available in this summary.
## Clinical Analysis & Structured Key Points
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[articles](https://www.nature.com/nm/articles?type=article) 4. article Determinants of response to CAR T cell therapy in a multicenter, multi-trial cohort analysis of patients with lymphoma [ Download PDF ](https://www.nature.com/articles/s41591-026-04707-w.pdf) [ Download PDF ](https://www.nature.com/articles/s41591-026-04707-w.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 23 October 2026 # Determinants of response to CAR T cell therapy in a multicenter, multi-trial cohort analysis of patients with lymphoma * [Justin Budka](https://www.nature.com/articles/s41591-026-04707-w#auth-Justin-Budka-Aff1) [ORCID: orcid.org/0000-0003-0908-1508](https://orcid.org/0000-0003-0908-1508)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1) [na1](https://www.nature.com/articles/s41591-026-04707-w#na1), * [Madison Davis](https://www.nature.com/articles/s41591-026-04707-w#auth-Madison-Davis-Aff1) [ORCID: orcid.org/0000-0002-1293-8974](https://orcid.org/0000-0002-1293-8974)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1) [na1](https://www.nature.com/articles/s41591-026-04707-w#na1), * [Subing Cao](https://www.nature.com/articles/s41591-026-04707-w#auth-Subing-Cao-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Jessica Ding](https://www.nature.com/articles/s41591-026-04707-w#auth-Jessica-Ding-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Jeremy Margaitis](https://www.nature.com/articles/s41591-026-04707-w#auth-Jeremy-Margaitis-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Wangshu Zhang](https://www.nature.com/articles/s41591-026-04707-w#auth-Wangshu-Zhang-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Joshua Winters](https://www.nature.com/articles/s41591-026-04707-w#auth-Joshua-Winters-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Saran Vardhanabhuti](https://www.nature.com/articles/s41591-026-04707-w#auth-Saran-Vardhanabhuti-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Yohei Arihara](https://www.nature.com/articles/s41591-026-04707-w#auth-Yohei-Arihara-Aff2-Aff3)[2](https://www.nature.com/articles/s41591-026-04707-w#Aff2),[3](https://www.nature.com/articles/s41591-026-04707-w#Aff3), * [Chad Williams](https://www.nature.com/articles/s41591-026-04707-w#auth-Chad-Williams-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Soumya Poddar](https://www.nature.com/articles/s41591-026-04707-w#auth-Soumya-Poddar-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Jerome Ritz](https://www.nature.com/articles/s41591-026-04707-w#auth-Jerome-Ritz-Aff3) [ORCID: orcid.org/0000-0001-5526-4669](https://orcid.org/0000-0001-5526-4669)[3](https://www.nature.com/articles/s41591-026-04707-w#Aff3), * [Mike Mattie](https://www.nature.com/articles/s41591-026-04707-w#auth-Mike-Mattie-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Priti Hegde](https://www.nature.com/articles/s41591-026-04707-w#auth-Priti-Hegde-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [David M. Barrett](https://www.nature.com/articles/s41591-026-04707-w#auth-David_M_-Barrett-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Rhine Shen](https://www.nature.com/articles/s41591-026-04707-w#auth-Rhine-Shen-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1), * [Simone Filosto](https://www.nature.com/articles/s41591-026-04707-w#auth-Simone-Filosto-Aff1)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1) & * … * [Davide Bedognetti](https://www.nature.com/articles/s41591-026-04707-w#auth-Davide-Bedognetti-Aff1) [ORCID: orcid.org/0000-0002-5857-773X](https://orcid.org/0000-0002-5857-773X)[1](https://www.nature.com/articles/s41591-026-04707-w#Aff1) Show authors [_Nature Medicine_](https://www.nature.com/nm) (2026) [Cite this article](https://www.nature.com/articles/s41591-026-04707-w#citeas) Save article [ View saved research ](https://www.nature.com/saved-research) ## Abstract In patients with non-Hodgkin lymphoma (NHL) treated with chimeric antigen receptor (CAR) T cell therapy, factors associated with efficacy overlap with prognostic biomarkers. Currently, there is no consensus on optimal product characteristics. We analyzed the phenotypic attributes of the anti-CD19 CAR T therapy axicabtagene ciloleucel (axi-cel) from 580 patients with NHL across multiple clinical trials with long-term follow-up (median, 41.9 months). A high proportion of naive-like (CCR7+CD45RA+) T cells was the most significant feature associated with prolonged progression-free survival (PFS; hazard ratio = 0.46, 95% confidence interval: 0.31−0.68, _P_ = 9.8 × 10−5, high versus low naive-like T cell groups) without impacting safety. The relationship between naive-like T cells and efficacy was independent of tumor microenvironment characteristics (assessed in 112 patients). In multivariate models, the naive-like phenotype outperformed clinicopathologic features such as inflammatory markers and tumor burden, remaining significant after adjusting for product expansion. An inverse correlation was observed between prior lines of therapy and the proportion of naive-like T cells in both product and matched apheresis samples, suggesting a benefit of earlier intervention. The key findings were validated in an independent cohort of 203 patients treated with axi-cel-based therapy or brexucabtagene autoleucel. Mass cytometry by time-of-flight analysis of products from a subgroup of 116 patients confirmed an association between a CD8 naive-like T cell phenotype lacking expression of exhaustion markers, such as TIGIT, LAG-3 and PD-1, and PFS. The evidence generated by this study has the potential to advance the development of more effective cellular therapies. ### Explore related subjects Discover the latest articles and news in related subjects. * [B-cell lymphoma](https://www.nature.com/subjects/b-cell-lymphoma) * [Cell delivery](https://www.nature.com/subjects/cell-delivery) * [Prognostic markers](https://www.nature.com/subjects/prognostic-markers) * [Translational immunology](https://www.nature.com/subjects/translational-immunology) * [Chimeric Antigen Receptor T-Cell Therapy in Hematological Malignancies](https://www.nature.com/subjects/chimeric-antigen-receptor-t-cell-therapy-in-hematological-malignancies) ## Main In patients with B cell NHL, multicenter trials investigating CAR T cell therapy directed against the B cell antigen CD19 have reported remarkable complete response rates, and long-term follow-up studies have demonstrated that many of these responses are highly durable, suggesting a curative potential[1](https://www.nature.com/articles/s41591-026-04707-w#ref-CR1 "Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 \(2023\)."). Axi-cel is an autologous anti-CD19 CAR T cell therapy used to treat patients with refractory or relapsed (R/R) large B cell lymphoma (LBCL) or follicular lymphoma (FL). Despite its encouraging efficacy, a proportion of patients do not achieve complete response (approximately 35−45% of patients with LBCL[2](https://www.nature.com/articles/s41591-026-04707-w#ref-CR2 "Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 \(2017\)."),[3](https://www.nature.com/articles/s41591-026-04707-w#ref-CR3 "Westin, J. R. et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N. Engl. J. Med. 389, 148–157 \(2023\)."),[4](https://www.nature.com/articles/s41591-026-04707-w#ref-CR4 "Jacobson, C. A. et al. Real-world evidence of axicabtagene ciloleucel for the treatment of large B cell lymphoma in the United States. Transplant. Cell. Ther. 28, 581.e1–581.e8 \(2022\)."),[5](https://www.nature.com/articles/s41591-026-04707-w#ref-CR5 "Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 \(2020\).") and 15−25% of those with FL[6](https://www.nature.com/articles/s41591-026-04707-w#ref-CR6 "Jacobson, C. et al. Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory \(R/R\) follicular lymphoma \(FL\). Hematol. Oncol. 41, 375–376 \(2023\)."),[7](https://www.nature.com/articles/s41591-026-04707-w#ref-CR7 "Neelapu, S. S. et al. Five-year follow-up analysis of ZUMA-5: axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma. J. Clin. Oncol. 43, 3573–3577 \(2025\).")) or relapse after an initial response. Large real-world analyses of patients treated with axi-cel reported associations between clinicopathologic features and outcome, such as poor performance status (Eastern Cooperative Oncology Group (ECOG))[4](https://www.nature.com/articles/s41591-026-04707-w#ref-CR4 "Jacobson, C. A. et al. Real-world evidence of axicabtagene ciloleucel for the treatment of large B cell lymphoma in the United States. Transplant. Cell. Ther. 28, 581.e1–581.e8 \(2022\)."),[5](https://www.nature.com/articles/s41591-026-04707-w#ref-CR5 "Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 \(2020\).") and elevated lactate dehydrogenase (LDH)[5](https://www.nature.com/articles/s41591-026-04707-w#ref-CR5 "Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 \(2020\)."). Soluble markers of systemic inflammation, such as C-reactive protein (CRP) and ferritin[8](https://www.nature.com/articles/s41591-026-04707-w#ref-CR8 "Faramand, R. G. et al. Baseline serum inflammatory proteins predict poor CAR T outcomes in diffuse large B-cell lymphoma. Blood Cancer Discov. 5, 106–113 \(2024\)."), and imaging-based measurement of tumor burden[9](https://www.nature.com/articles/s41591-026-04707-w#ref-CR9 "Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 4898–4911 \(2020\)."),[10](https://www.nature.com/articles/s41591-026-04707-w#ref-CR10 "Locke, F. L. et al. Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume. Blood 143, 2464–2473 \(2024\)."),[11](https://www.nature.com/articles/s41591-026-04707-w#ref-CR11 "Dean, E. A. et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 3268–3276 \(2020\).") have also been associated with poor outcome to axi-cel[8](https://www.nature.com/articles/s41591-026-04707-w#ref-CR8 "Faramand, R. G. et al. Baseline serum inflammatory proteins predict poor CAR T outcomes in diffuse large B-cell lymphoma. Blood Cancer Discov. 5, 106–113 \(2024\)."),[9](https://www.nature.com/articles/s41591-026-04707-w#ref-CR9 "Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 4898–4911 \(2020\)."),[10](https://www.nature.com/articles/s41591-026-04707-w#ref-CR10 "Locke, F. L. et al. Axicabtagene ciloleucel vs standard of care in second-line large B-cell lymphoma: outcomes by metabolic tumor volume. Blood 143, 2464–2473 \(2024\)."),[11](https://www.nature.com/articles/s41591-026-04707-w#ref-CR11 "Dean, E. A. et al. High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 3268–3276 \(2020\)."). Recently, a large analysis of patients with NHL treated with different CAR T cell therapies corroborated the importance of systemic inflammation in limiting CAR T cell efficacy[12](https://www.nature.com/articles/s41591-026-04707-w#ref-CR12 "Raj, S. S. et al. An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma. Nat. Med. 31, 1183–1194 \(2025\)."). However, parameters captured by these analyses, such as CRP, ferritin and LDH, have been associated with unfavorable prognosis outside CAR T cell treatment[13](https://www.nature.com/articles/s41591-026-04707-w#ref-CR13 "Saowapa, S. et al. Ferritin level as a prognostic marker for non-Hodgkin lymphoma: a systematic review and meta-analysis. Blood 144, 6448 \(2024\)."),[14](https://www.nature.com/articles/s41591-026-04707-w#ref-CR14 "Kawaguchi, Y. et al. Elevated C-reactive protein level is associated with poor prognosis in follicular lymphoma patients undergoing rituximab-containing chemotherapy. Int. J. Hematol. 112, 341–348 \(2020\)."),[15](https://www.nature.com/articles/s41591-026-04707-w#ref-CR15 "Sehn, L. H. et al. The revised International Prognostic Index \(R-IPI\) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109, 1857–1861 \(2007\)."), therefore preventing causal inference and offering limited insight in terms of therapeutic actionability. Knowledge regarding the impact of product characteristics on the long-term benefit of anti-CD19 CAR T cell therapy in hematological malignancies is fragmentary[1](https://www.nature.com/articles/s41591-026-04707-w#ref-CR1 "Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 \(2023\)."),[16](https://www.nature.com/articles/s41591-026-04707-w#ref-CR16 "Tao, Z. et al. Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies. Blood Cancer J. 14, 213 \(2024\)."). Exploratory studies have suggested links between outcomes and parameters such as T cell exhaustion signatures[17](https://www.nature.com/articles/s41591-026-04707-w#ref-CR17 "Deng, Q. et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat. Med. 26, 1878–1887 \(2020\)."), early memory[9](https://www.nature.com/articles/s41591-026-04707-w#ref-CR9 "Locke, F. L. et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 4, 4898–4911 \(2020\)."),[18](https://www.nature.com/articles/s41591-026-04707-w#ref-CR18 "Bai, Z. et al. Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL. Sci. Adv. 8, eabj2820 \(2022\)."),[19](https://www.nature.com/articles/s41591-026-04707-w#ref-CR19 "Filosto, S. et al. Product attributes of CAR T-cell therapy differentially associate with efficacy and toxicity in second-line large B-cell lymphoma \(ZUMA-7\). Blood Cancer Discov. 5, 21–33 \(2024\).") and T regulatory subsets[20](https://www.nature.com/articles/s41591-026-04707-w#ref-CR20 "Haradhvala, N. J. et al. Distinct cellular dynamics associated
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