# T-cell exhaustion and CAR-T persistence

Source: https://onco.cc/terms/t-cell-exhaustion-term/  
OnCo record `t-cell-exhaustion-term` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Immune T cells that have been fighting too long become 'exhausted': sluggish, covered in inhibitory receptors, unable to kill. It limits both the patient's natural anti-tumour response and how long engineered CAR-T cells keep working (persistence).

## Summary

Exhaustion is driven by chronic antigen exposure and marked by PD-1, TIM-3, LAG-3 and TOX expression; checkpoint inhibitors partly reverse it, which is their mechanism. For CAR-T, the fitness of the patient's starting T cells (damaged by prior chemotherapy, especially bendamustine) predicts expansion and response, and peak expansion and persistence correlate with durable remission; ongoing B-cell aplasia is a convenient marker that CD19 CAR-T cells are still active. Engineering answers include 4-1BB costimulation (longer persistence than CD28), armoured CARs, knockout of exhaustion-associated genes, and collecting cells earlier in the disease course. Persistence matters less when the tumour is eliminated quickly, as in ALL.

## Fields

- Kind: Term
- Last checked: 2026-09-09
- Also known as: exhaustion; exhausted T cells; T-cell fitness; T cell fitness; T-cell dysfunction; CAR-T persistence; CAR persistence; CAR-T expansion; peak expansion; in vivo expansion; B-cell aplasia; loss of persistence; memory phenotype; stem-like T cells

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/T_cell_exhaustion
- Wikipedia: https://en.wikipedia.org/wiki/T_cell_exhaustion

## Connected records

- terms: [Antigen escape (antigen loss, lineage switch)](https://onco.cc/terms/antigen-escape/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Hypogammaglobulinaemia and infection risk after B-cell therapies](https://onco.cc/terms/hypogammaglobulinaemia/)
- fronts: [Cell Therapy](https://onco.cc/fronts/cell-therapy/), [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Armoured, logic-gated & next-gen CARs](https://onco.cc/technologies/armored-car/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [CD57](https://onco.cc/targets/cd57/), [CD69](https://onco.cc/targets/cd69/), [CD8](https://onco.cc/targets/cd8/), [LAG-3](https://onco.cc/targets/lag3/), [PD-1](https://onco.cc/targets/pd1/), [TIGIT](https://onco.cc/targets/tigit/), [TIM-3](https://onco.cc/targets/tim3/)
- drugs: [AZD7789](https://onco.cc/drugs/azd7789/), [Cobolimab](https://onco.cc/drugs/cobolimab/), [Domvanalimab](https://onco.cc/drugs/domvanalimab/), [Favezelimab](https://onco.cc/drugs/favezelimab/), [Fianlimab](https://onco.cc/drugs/fianlimab/), [HB0036](https://onco.cc/drugs/hb0036/), [HLX26](https://onco.cc/drugs/hlx26/), [LB1410](https://onco.cc/drugs/lb1410/), [Relatlimab + nivolumab](https://onco.cc/drugs/relatlimab-nivolumab/), [Rilvegostomig](https://onco.cc/drugs/rilvegostomig/), [Tiragolumab](https://onco.cc/drugs/tiragolumab/), [Vibostolimab](https://onco.cc/drugs/vibostolimab/)
- trials: [A Clinical Study to Evaluate the Efficacy and Safety of HLX26 (Anti-LAG-3 Monoclonal Antibody Injection) Combined With Serplulimab and Chemotherapy in Previously Untreated Advanced NSCLC Patients](https://onco.cc/trials/nct05787613/), [A Global Phase III Study of Rilvegostomig or Pembrolizumab Monotherapy for First-Line Treatment of PD-L1-high Metastatic Non-small Cell Lung Cancer](https://onco.cc/trials/nct06868277/), [A Global Phase III Study of Rilvegostomig or Pembrolizumab Plus Chemotherapy for First-Line Treatment of Locally Advanced or Metastatic Non-Squamous N](https://onco.cc/trials/nct06627647/), [A Global Phase III Study of Rilvegostomig or Pembrolizumab Plus Chemotherapy for First-Line Treatment of Locally Advanced or Metastatic Squamous Non-s](https://onco.cc/trials/nct06692738/), [A Global Study to Assess the Effects of Durvalumab + Domvanalimab Following Concurrent Chemoradiation in Participants With Stage III Unresectable NSCLC](https://onco.cc/trials/nct05211895/), [A Phase I/IIa Study of AZD8205 Given Alone or Combined, in Participants With Advanced/Metastatic Solid Malignancies](https://onco.cc/trials/nct05123482/), [A Phase II Platform Study to Evaluate Treatment With Cemiplimab Monotherapy or Cemiplimab Plus Fianlimab or Other Novel Combinations in Patients With Colorectal](https://onco.cc/trials/nct07058012/), [A Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer](https://onco.cc/trials/nct06764875/), [A Phase III, Randomised Study of Adjuvant Dato-DXd in Combination With Rilvegostomig or Rilvegostomig Monotherapy Versus Standard of Care, Following C](https://onco.cc/trials/nct06564844/), [A Platform Study in Non-Small Cell Lung Cancer (NSCLC)](https://onco.cc/trials/nct06996782/), [A Platform Study of Novel Immunotherapy Combinations as First-Line Treatment in Participants With PD-L1 Positive Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck- GALAXIES H&N-202](https://onco.cc/trials/nct06062420/), [A Platform Study of Novel Immunotherapy Combinations in Participants With Previously Untreated, Advanced/Metastatic Non-Small-Cell Lung Cancer](https://onco.cc/trials/nct05565378/), [A Safety and Efficacy Study of Treatment Combinations With and Without Chemotherapy in Adult Participants With Advanced Upper Gastrointestinal Tract Malignancies](https://onco.cc/trials/nct05329766/), [A Study Assessing KB707 for the Treatment of Locally Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct05970497/), [A Study Evaluating Atezolizumab and Bevacizumab, With or Without Tiragolumab, in Participants With Untreated Locally Advanced or Metastatic Hepatocell](https://onco.cc/trials/nct05904886/), [A Study Evaluating Different Immunotherapies (LAG-3 and PD-1 With or Without TIGIT, Compared to PD-L1 Alone) in Participants With Untreated Locally Advanced Metastatic Urothelial Cancer](https://onco.cc/trials/nct05645692/), [A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Advanced Liver Cancers (Morpheus-Li](https://onco.cc/trials/nct04524871/), [A Study Evaluating the Safety and Efficacy of HB0036 in Subjects With Advanced Solid Tumors](https://onco.cc/trials/nct05417321/), [A Study of Atezolizumab With or Without Tiragolumab Following Neoadjuvant Chemoradiotherapy in Participants With Locally Advanced Rectal Cancer](https://onco.cc/trials/nct05009069/), [A Study of AZD2936 Anti-TIGIT/Anti-PD-1 Bispecific Antibody in Participants With Advanced or Metastatic NSCLC](https://onco.cc/trials/nct04995523/), [A Study of Belrestotug Plus Dostarlimab Compared With Placebo Plus Pembrolizumab in Previously Untreated Participants With Programmed Death Ligand 1 (PD-L1) High Non-small-cell Lung Cancer (NSCLC)](https://onco.cc/trials/nct06472076/), [A Study of BMS-986482 Alone or as Combination Therapy in Participants With Advanced Solid Tumors](https://onco.cc/trials/nct06697197/), [A Study of BMS-986504 Monotherapy and in Combination With Other Agents in Participants With Advanced and/or Metastatic Solid Tumors With Homozygous MTAP Deletion (MountainTAP-5)](https://onco.cc/trials/nct07492680/), [A Study of Cobolimab Plus Dostarlimab in Pediatric and Young Adult Participants With Cancer](https://onco.cc/trials/nct06521567/), [A Study of Efficacy and Safety of Pembrolizumab Plus Enfortumab Vedotin (EV) +/- Investigational Agents in First-Line Metastatic Urothelial Carcinoma (mUC) (MK-3475-04B/KEYMAKER-U04)](https://onco.cc/trials/nct05845814/), [A Study of Immune Checkpoint Inhibitor Combinations With Axitinib in Participants With Untreated Locally Advanced Unresectable or Metastatic Renal Cel](https://onco.cc/trials/nct05805501/), [A Study of Novel Agents or Combinations as Perioperative Treatment in Participants With Locally Advanced Resectable Gastroesophageal Adenocarcinoma](https://onco.cc/trials/nct07069712/), [A Study of Novel Combinations in Non-Small Cell Lung Cancer (NSCLC)](https://onco.cc/trials/nct07098338/), [A Study of Rilvegostomig or Durvalumab Plus Chemotherapy for First-Line Treatment of Biliary Tract Cancer (ARTEMIDE-Biliary02)](https://onco.cc/trials/nct07221253/), [A Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination (FDC) in Previously Untreated Metastatic or Unresectable Melanoma](https://onco.cc/trials/nct05625399/), [A Study to Assess the Safety and Efficacy of AZD7789 in Participants With Advanced or Metastatic Solid Cancer](https://onco.cc/trials/nct04931654/), [A Study to Compare the Efficacy of Nivolumab and Relatlimab Plus Chemotherapy vs Pembrolizumab Plus Chemotherapy for Stage IV/Recurrent Non-squamous N](https://onco.cc/trials/nct06561386/), [A Study to Evaluate LB1410 in Combination With LB4330 in Patients With Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct06468358/), [A Study to Evaluate Whether Participants With Melanoma Prefer Subcutaneous vs Intravenous Administration of Nivolumab and Nivolumab + Relatlimab Fixed](https://onco.cc/trials/nct06101134/), [A Study to Explore the Reasonable Dosage and Evaluate the Efficacy, Safety and Tolerability of HLX10 and HLX04 with or Without HLX53 in Untreated, Locally Advanced or Metastatic Hepatocellular Carcinoma Patients.](https://onco.cc/trials/nct06349980/), [A Study to Find Out How Safe REGN5668 is and How Well it Works In Adult Women When Given With Either Cemiplimab, or Cemiplimab + Fianlimab, or Ubamata](https://onco.cc/trials/nct04590326/), [A Study to Investigate Safety of AZD6750 in Adult Participants With Select Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct07115043/), [A Study to Learn if a Combination of Fianlimab and Cemiplimab Versus Cemiplimab Alone is More Effective for Adult Participants With Advanced Non-Small](https://onco.cc/trials/nct05785767/), [A Study to See if Giving Fianlimab and Cemiplimab Together is Better Than Cemiplimab Alone at Treating Recurrent or Metastatic Head and Neck Squamous ](https://onco.cc/trials/nct06769698/), [A Study With Combinations of Anti-LAG-3 and Anti-PD-1 Antibodies in Adult Participants With Advanced or Metastatic Melanoma (Harmony Head-to-Head)](https://onco.cc/trials/nct06246916/), [A Trial to Learn How the Combination of Fianlimab With Cemiplimab and Chemotherapy Works Compared With Cemiplimab and Chemotherapy for Treating Adult ](https://onco.cc/trials/nct05800015/), [A Trial to Learn if Fianlimab and Cemiplimab Are Safe and Work Better Than Anti-PD1 Alone in Adult Participants With Resectable Stage 3 or 4 Melanoma](https://onco.cc/trials/nct06190951/), [A Trial to Learn if the Combination of Fianlimab, Cemiplimab, and Chemotherapy is Safe and Works Better Than the Combination of Cemiplimab and Chemoth](https://onco.cc/trials/nct06161441/), [A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back Af](https://onco.cc/trials/nct05608291/), [AK129 Combination Therapy for Advanced Solid Tumors](https://onco.cc/trials/nct06943820/), [An Open-label Study to Investigate the Efficacy and Safety of Dato-DXd + Rilvegostomig vs SoC in Adult Participants With High-risk MIUC](https://onco.cc/trials/nct07720284/), [Capecitabine/Oxaliplatin Chemotherapy and Cemiplimab With or Without Fianlimab or REGN7075 in Locally Advanced Rectal Cancer](https://onco.cc/trials/nct07281768/), [Cemiplimab With Fianlimab for Resectable Non-Metastatic Colon Cancer](https://onco.cc/trials/nct07224022/), [Cemiplimab With or Without Fianlimab to Treat Older Patients With Localized or Locally Advanced MSI-H Colorectal Cancer](https://onco.cc/trials/nct06205836/), [CheckMate 142](https://onco.cc/trials/checkmate-142/), [CheckMate 358](https://onco.cc/trials/checkmate-358/), [Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer](https://onco.cc/trials/nct04082364/), [DESTINY-Endometrial01: A Phase III Study of Trastuzumab Deruxtecan Plus Rilvegostomig or Pembrolizumab as First-Line Treatment of HER2-Expressing (IHC](https://onco.cc/trials/nct06989112/), [Domvanalimab and Zimberelimab in Advanced Liver Cancers](https://onco.cc/trials/nct05724563/), [Efficacy Comparison of Cobolimab + Dostarlimab + Docetaxel to Dostarlimab + Docetaxel to Docetaxel Alone in Participants With Advanced Non-small Cell Lung Cancer Who Have Progressed on Prior Anti-PD-(L)1 Therapy and Chemotherapy](https://onco.cc/trials/nct04655976/), [Evaluation of Co-formulated Pembrolizumab/Quavonlimab (MK-1308A) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) ](https://onco.cc/trials/nct04895722/), [Fianlimab + cemiplimab phase 3 (first-line melanoma)](https://onco.cc/trials/fianlimab-phase3-melanoma/), [I-SPY 2](https://onco.cc/trials/i-spy-2/), [Investigation of Ubamatamab Combination Therapy in Adult Participants With Platinum-Resistant Ovarian Cancer](https://onco.cc/trials/nct06787612/), [KEYMAKER-U01 Substudy 01A: Efficacy and Safety Study of Pembrolizumab (MK-3475) With or Without Chemotherapy When Used With Investigational Agents in Treatment-naïve Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A/KEYMAKER-U01A)](https://onco.cc/trials/nct04165070/), [Long-term Safety and Efficacy Extension Study for Participants With Advanced Tumors Who Are Currently on Treatment or in Follow-up in a Pemb](https://onco.cc/trials/nct03486873/), [Neoadjuvant Cemiplimab for the Treatment of Resectable NSCLC, HCC, and HNSCC in Adult Patients](https://onco.cc/trials/nct03916627/), [Novel Combinations in Participants With Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma](https://onco.cc/trials/nct05702229/), [NOvel Immunotherapy Strategies for Advanced Triple Negative Breast Cancer (TNBC) Patients: TONIC-3 Trial](https://onco.cc/trials/nct06342037/), [Pan Tumor Rollover Study](https://onco.cc/trials/nct03899155/), [Pembrolizumab/Vibostolimab (MK-7684A) or Atezolizumab in Combination With Chemotherapy in First Line Treatment of Extensive-Stage Small Cell Lung Cancer (MK-7684A-008/KEYVIBE-008)](https://onco.cc/trials/nct05224141/), [Phase 3 Study of T-DXd and Rilvegostomig Versus SoC in Advanced HER2-expressing Biliary Tract Cancer](https://onco.cc/trials/nct06467357/), [Phase III Study of Rilvegostomig in Combination With Bevacizumab With or Without Tremelimumab as First-line Treatment of Hepatocellular Carcinoma](https://onco.cc/trials/nct06921785/), [Phase III, Open-label, Study of First-line Dato-DXd in Combination With Rilvegostomig for Advanced Non-squamous NSCLC With High PD-L1 Expression (TC ≥](https://onco.cc/trials/nct06357533/), [RELATIVITY-047](https://onco.cc/trials/relativity-047/), [RELATIVITY-098](https://onco.cc/trials/relativity-098/), [Rilvegostomig + Chemotherapy as Adjuvant Therapy for Biliary Tract Cancer After Resection (ARTEMIDE-Biliary01)](https://onco.cc/trials/nct06109779/), [Saci Nivo Rela for TNBC](https://onco.cc/trials/nct06963905/), [Safety and Efficacy Study of Investigational Agents as Monotherapy or in Combination With Pembrolizumab (MK-3475) for the Treatment of Extensive-Stage Small Cell Lung Cancer (ES-SCLC) in Need of Second-Line Therapy (MK-3475-B98/KEYNOTE-B98)](https://onco.cc/trials/nct04938817/), [Sonesitatug Vedotin in Combination With Capecitabine With or Without Rilvegostomig in Participants With Advanced or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma Expressing Claudin18.2](https://onco.cc/trials/nct07431281/), [Study Evaluating Effectiveness and Safety of Zimberelimab and Domvanalimab in Lung Cancer](https://onco.cc/trials/nct04736173/), [Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Participants With Untreated Extensive-Stage Small Cell Lung Cancer](https://onco.cc/trials/nct04665856/), [Study of Dato-DXd as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Tumours (TROPION-PanTumor03)](https://onco.cc/trials/nct05489211/), [Study of Novel Immunomodulators as Monotherapy and in Combination With Anticancer Agents in Participants With Advanced Hepatobiliary Cancer](https://onco.cc/trials/nct05775159/), [Study of Novel Treatment Combination Therapies in Participants With Head and Neck Squamous Cell Carcinoma Regardless of PD-L1 Expression Status; Subst](https://onco.cc/trials/nct06727565/), [Study of Novel Treatment Combinations in Patients With Lung Cancer](https://onco.cc/trials/nct05633667/), [Study of Retinfanlimab in Combination With INCAGN02385 and INCAGN02390 as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck](https://onco.cc/trials/nct05287113/), [Study With Various Immunotherapy Treatments in Participants With Lung Cancer](https://onco.cc/trials/nct05676931/), [Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)](https://onco.cc/trials/nct04626479/), [Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03)](https://onco.cc/trials/nct04626518/), [Thoracic Radiotherapy and Inhibition of PD-1 and LAG-3 for Locally Advanced Non-Small Cell Lung Cancer](https://onco.cc/trials/nct06865339/), [VO and Nivolumab vs Physician's Choice in Advanced Melanoma That Progressed on Anti-PD-1 & Anti-CTLA-4 Drugs [IGNYTE-3]](https://onco.cc/trials/nct06264180/), [Zimberelimab and Domvanalimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Patients With Untreated Metastatic Non-Small Cell Lung Cancer](https://onco.cc/trials/nct05502237/)

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