Open research questions in CAR-T cell therapy research
1,136 gap statements mined from CAR-T cell therapy research papers in our 7.9M-paper local library, which holds 5,924 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The need for a comprehensive review of the incidence, biological plausibility, and clinical relevance of lymphomas arising after CAR T-cell therapy. The importance of developing practical recommendations for surveillance and patient counseling.
The epidemiology of RVI in hematopoietic cell transplant and chimeric antigen receptor T-cell therapy recipients is not well understood. There is a need to investigate the post-pandemic RVI epidemiology in these patients.
Epidemiology of respiratory viral infections among hematopoietic cellular therapy and chimeric antigen receptor T-cell therapy recipients in the post COVID-19 era · 2026 · DOIThe lack of leukemia-specific surface markers for CAR T cell therapy in AML. The potential for on-target off-tumor toxicities due to the expression of target antigens on healthy myeloid cells and hematopoietic progenitor cells. The need to improve the efficacy of CAR-T cell therapy in AML while minimizing toxicities.
Immune checkpoint knockout screen reveals TIGIT-CD155 interaction as a significant modulator of adapter CAR-T cell function in acute myeloid leukemia · 2026 · DOILimited clinical experience with T-cell redirecting therapies. Applicability in only a limited number of patients.
Rheumatologists’ expectations and perceptions of T-cell redirecting therapies: results from a cross-sectional survey · 2026 · DOIPractical markers available before infusion are still limited. The prognostic value of pretreatment PNI in patients treated with TanCAR7 is unclear.
Pretreatment Prognostic Nutritional Index Is Associated with Treatment Response and Survival in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Receiving CAR-T Cell Therapy · 2026 · DOILimited access to adoptive cellular therapies in Australia. Limited understanding of the mechanisms of action and toxicity profiles of ACT. Need for more effective and targeted therapies for malignancies.
An Australian Narrative Review of Adoptive Cellular Therapies in Malignancy: Expanding Indications, Referral Pathways and Safety Beyond Specialist Centres · 2026 · DOIThe clinical development portfolio of CAR/TCR-engineered cellular therapies in musculoskeletal sarcomas is heterogeneous and not well characterized. There is a need to separate engineered-receptor products from other cell-based immunotherapies.
Clinical development landscape of CAR/TCR-engineered cellular therapies in musculoskeletal sarcomas: a TrialTrove-based registry analysis · 2026 · DOIThe authors note the challenge of developing effective treatments for CAR-T-associated parkinsonism, which is generally unresponsive to levodopa and often has limited response to corticosteroids.
Interpreting DIC scores in CAR T-cell patients is challenging due to treatment-related cytopenias and the effects of IL-6 receptor blockade. Distinguishing between inflammation-driven consumption and reduced fibrinogen synthesis following IL-6 receptor blockade. Balancing the risk of clinical thrombohemorrhagic complications with the need for CRS-directed therapies.
Dynamics and clinical significance of coagulation abnormalities following CAR T-cell therapy · 2026 · DOIOne of the challenges is the limited durability of responses to CAR-T therapy. Another challenge is the risk of antigen escape, which can lead to treatment failure. The paper also highlights the importance of understanding the mechanisms of resistance to guide treatment selection, which is a technical challenge.
One challenge is the potential risk of integration-mediated malignant transformation of CAR-T cells. Another challenge is the need for targeted integration of genes of interest. The transient nature of gene transfer using non-integrating vectors is also a challenge.
The clinical utility of PD-L1 expression assessment in cutaneous melanoma is controversial. The interpretation of PD-L1 scores in clinical practice is still a matter of debate. The correlation between PD-L1 expression and response to anti-PD-1/anti-PD-L1 immunotherapy is not fully understood.
Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship · 2024 · DOIThe need to reduce time, costs, and laboratory animal use in scFv selection. The challenge of modeling interactions between monoclonal antibodies and target antigens.
Artificial Intelligence-Powered Molecular Docking and Steered Molecular Dynamics for Accurate scFv Selection of Anti-CD30 Chimeric Antigen Receptors · 2024 · DOIOne of the major technical hurdles involved in growing suspension cells under microfluidic conditions is their immobilization, to avoid washing them out of the microfluidic chip during medium renewal. The CAR-T cell manufacturing process continues to be very complex and expensive due to the variability of the starting material.
Implementing a digital assessment of tumor PD-L1 expression could facilitate diagnostic procedures and enhance the accuracy of treatment outcome prognostication in patients with metastatic melanoma.
Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship · 2024 · DOIThe study was conducted in a limited number of cell lines and patient samples, - The study did not investigate the long-term effects of TIGIT KO on AdCAR-T cells, - The study did not examine the potential off-target effects of TIGIT KO, - The study was designed and conducted in accordance with the principles of the Declaration…
Immune checkpoint knockout screen reveals TIGIT-CD155 interaction as a significant modulator of adapter CAR-T cell function in acute myeloid leukemia · 2026 · DOIThe study had a limited sample size, - The number of events was limited, - The apparent time-varying effect of PNI should be considered, - The results should be interpreted…
Pretreatment Prognostic Nutritional Index Is Associated with Treatment Response and Survival in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma Receiving CAR-T Cell Therapy · 2026 · DOIInvestigating actual sarcoma enrollment and dedicated sarcoma cohorts, - Expanding the study to multiple registries, - Analyzing patient-level efficacy and safety…
Clinical development landscape of CAR/TCR-engineered cellular therapies in musculoskeletal sarcomas: a TrialTrove-based registry analysis · 2026 · DOICAR-T cell therapy has disadvantages or limitations, including relapse caused by antigen lose, lacking tumor specific antigens, poor persistence and infiltration, high…
SMAD4 Regulates the Expression of LCK Affecting Chimeric Antigen Receptor‐T Cells Proliferation Through PI3K/Akt Signaling Pathway · 2025 · DOIThe transient nature of gene transfer to engineered cells, - The risk of insertional oncogenesis, genomic translocations, and rearrangements, - The limited understanding of targeting mechanisms and off-target…
Investigation of CAR-T-cell therapy in larger SLE patient populations, - Exploration of optimal CAR-T-cell dosing regimens, - Study of long-term efficacy and safety of CAR-T-cell therapy in SLE…
Complexity of cancer disease, - Tumor progression and recurrence, - Drug resistance, - Side effects of therapy, - Limited understanding of tumor…
Investigation of nanocarriers for cancer treatment, - Development of targeting strategies, - Exploration of nanomedicine for diagnosis and monitoring, - Study of the interaction between tumor cells and the immune…
Further validation of the predicted protein structures, - Investigation of the binding mechanisms and potential clinical behavior of novel molecules, - Reducing costs for research and development to decrease the CAR-T cell…
Artificial Intelligence-Powered Molecular Docking and Steered Molecular Dynamics for Accurate scFv Selection of Anti-CD30 Chimeric Antigen Receptors · 2024 · DOIFurther research is required to fully comprehend the particular side effects of immunomodulation, - Research to ascertain the best order and combination of this medication with conventional chemotherapy and targeted therapies, - Investigation to find reliable predictive…
Advancements in Personalized CAR-T Therapy: Comprehensive Overview of Biomarkers and Therapeutic Targets in Hematological Malignancies · 2024 · DOI
Most-cited papers in CAR-T cell therapy research
- Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma · New England Journal of Medicine · 2017 · 5,508 citations
- Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia · New England Journal of Medicine · 2014 · 4,901 citations
- Enhancement of Antitumor Immunity by CTLA-4 Blockade · Science · 1996 · 3,317 citations
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia · New England Journal of Medicine · 2011 · 3,144 citations
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia · New England Journal of Medicine · 2013 · 3,059 citations
- CAR T cell immunotherapy for human cancer · Science · 2018 · 2,952 citations
- CAR-T cell therapy: current limitations and potential strategies · Blood Cancer Journal · 2021 · 2,767 citations
- A Gene Encoding an Antigen Recognized by Cytolytic T Lymphocytes on a Human Melanoma · Science · 1991 · 2,638 citations
- T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial · The Lancet · 2014 · 2,614 citations
- Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia · New England Journal of Medicine · 2018 · 2,448 citations
Most recent work
- CD19 CAR-T cells for treatment-refractory autoimmune diseases: the phase 1/2 CASTLE basket trial · Nature Medicine · 2026
- In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study · Nature Medicine · 2026
- Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction–associated steatohepatitis · Science Translational Medicine · 2026
- Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth · Cancer Cell · 2026
- Engineered outer membrane vesicles enhance solid tumour CAR-T cell therapy · Nature Biomedical Engineering · 2026
- In vivo engineering of CAR-T cells: delivery strategies and clinical translation · Biomarker Research · 2026
- CD4+ T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy · Nature Medicine · 2026
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities · Advanced Science · 2026
- Anti-CD19 CAR T cells for pediatric patients with treatment-refractory autoimmune diseases · Nature Medicine · 2026
- BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial · Nature Medicine · 2026
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