header banner
Default

Mechanisms of chimeric antigen receptor-T cell resistance in hematological malignancies - Nature Reviews Drug Discovery


Table of Contents
  • Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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). Together with Schuster et al. (2017), this seminal study validated the efficacy of anti-CD19 CAR-T cell therapy in patients with R/R lymphoma and showed a similar complete response rate (approximately 60%), despite differences in the CAR design and lymphodepletion regimens, setting a new standard of care for patients with R/R lymphomas.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018). This study shows the long-term remission rates achieved by tisa-cel (Kymriah, Novartis), a lentiviral-transduced second-generation CD19 CAR-T cell product containing a 4-1BB co-stimulatory domain. This product became the first FDA-approved gene therapy in 2017, when it received approval for paediatric and young adult patients with B-ALL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Abramson, J. S. et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 396, 839–852 (2020).

    Article  PubMed  Google Scholar 

  • Wang, M. et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 382, 1331–1342 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shah, B. D. et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood 138, 11–22 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Munshi, N. C. et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N. Engl. J. Med. 384, 705–716 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314–324 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Jacobson, C. A. et al. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J. Clin. Oncol. 38, 3095–3106 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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).

    Article  PubMed Central  PubMed  Google Scholar 

  • Baird, J. H. et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Adv. 5, 143–155 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  • Logue, J. M. et al. Cytopenia following axicabtagene ciloleucel (axi-cel) for refractory large B-cell lymphoma (LBCL). J. Clin. Oncol. 37, e14019 (2019).

    Article  Google Scholar 

  • Schuster, S. J. et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 22, 1403–1415 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Iacoboni, G. et al. Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Cancer Med. 10, 3214–3223 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang, M. et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J. Clin. Oncol. 41, 555–567 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Jacobson, C. A. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 23, 91–103 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Chong, E. A., Ruella, M., Schuster, S. J. & Lymphoma Program Investigators at the University of Pennsylvania. Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N. Engl. J. Med. 384, 673–674 (2021). Together with Schuster et al. (2021), this study shows long-term remissions in patients who received tisa-cel for lymphoma (DLBCL, follicular lymphoma and high-grade BCL). The studies demonstrate a complete response rate of 39% and 55%, respectively, with >60% of these patients remaining in remission at 5 years.

    Article  PubMed  Google Scholar 

  • Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, 31–42 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Laetsch, T. W. et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J. Clin. Oncol. 41, 1664–1669 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  • Pasquini, M. C. et al. Post-marketing use outcomes of an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, axicabtagene ciloleucel (Axi-Cel), for the treatment of large B cell lymphoma (LBCL) in the United States (US). Blood 134, 764–764 (2019).

    Article  Google Scholar 

  • Riedell, P. A. et al. A multicenter analysis of outcomes, toxicities, and patterns of use with commercial axicabtagene ciloleucel and tisagenlecleucel for relapsed/refractory aggressive B-cell lymphomas. Blood 138, 2512 (2021).

    Article  Google Scholar 

  • Pasquini, M. C. et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 4, 5414–5424 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Neelapu, S. S. et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood 141, 2307–2315 (2023).

    CAS  PubMed  Google Scholar 

  • Jacobson, C. et al. Long-term (≥4 year and ≥5 year) overall survival (OS) by 12- and 24-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma (LBCL). Blood 138, 1764 (2021).

    Article  Google Scholar 

  • Sehgal, A. et al. Lisocabtagene maraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): primary analysis from the phase 2 PILOT study. J. Clin. Oncol. 40, 7062–7062 (2022).

    Article  Google Scholar 

  • Grupp, S. A. et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood 132, 895 (2018).

    Article  Google Scholar 

  • Anderson, L. D. et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, for the treatment of patients with relapsed and refractory multiple myeloma: updated results from KarMMa. J. Clin. Oncol. 39, 8016 (2021).

    Article  Google Scholar 

  • Davis, J., McGann, M., Shockley, A. & Hashmi, H. Idecabtagene vicleucel versus ciltacabtagene autoleucel: a Sophie’s choice for patients with relapsed refractory multiple myeloma. Expert Rev. Hematol. 15, 473–475 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Martin, T. et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J. Clin. Oncol. 41, 1265–1274 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  • Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018). This ground-breaking study used genomic and functional techniques to gain significant insights into the factors that influence the response of CD19 CAR-T cell therapy in patients with CLL. Of note, the study identified IL-6/STAT3 signatures within the T cells of responders, shedding light on crucial biomarkers that can be used by physicians to predict treatment outcomes in patients with CLL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Curran, K. J. et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood 134, 2361–2368 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Cappell, K. M. et al. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J. Clin. Oncol. 38, 3805–3815 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Vercellino, L. et al. Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma. Blood Adv. 4, 5607–5615 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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).

    Article  PubMed Central  PubMed  Google Scholar 

  • Hay, K. A. et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood 133, 1652–1663 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chan, J. D. et al. Cellular networks controlling T cell persistence in adoptive cell therapy. Nat. Rev. Immunol. 21, 769–784 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Xia, A., Zhang, Y., Xu, J., Yin, T. & Lu, X. J. T cell dysfunction in cancer immunity and immunotherapy. Front. Immunol. 10, 1719 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell. Mol. Immunol. 17, 27–35 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Woo, S. R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).

    Article  CAS  PubMed  Google Scholar 

  • Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    Article  CAS  PubMed  Google Scholar 

  • Chauvin, J. M. et al. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Invest. 125, 2046–2058 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  • Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 1130–1144 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 1039–1041 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • van Bruggen, J. A. C. et al. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood 134, 44–58 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Rossi, J. et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 132, 804–814 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klebanoff, C. A. et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318–334 (2016).

    Article  PubMed  Google Scholar 

  • Arcangeli, S. et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J. Clin. Invest. 132, e150807 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Larson, R. C. & Maus, M. V. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat. Rev. Cancer 21, 145–161 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lutz, E. R. et al. Superior efficacy of CAR-T cells using marrow-infiltrating lymphocytes (MILs) as compared to peripheral blood lymphocytes (PBLs). Blood 134, 4437 (2019).

    Article  Google Scholar 

  • Garfall, A. L. et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 3, 2812–2815 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ruella, M. et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 24, 1499–1503 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Neelapu, S. S. et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat. Med. 28, 735–742 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ghassemi, S. et al. Rapid manufacturing of non-activated potent CAR T cells. Nat. Biomed. Eng. 6, 118–128 (2022). This paper pinpoints an optimized and shortened manufacturing protocol of CAR-T cells that offers the advantage of reducing manufacturing costs and the generation of non-activated CAR-T cells with higher antileukaemic activity.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019). In this study, new epigenetic and genetic characteristics associated with CAR-T cell exhaustion are discovered. The paper describes the critical role of the transcription factor component JUN (part of the canonical AP-1 FOS–JUN heterodimer) in preventing exhaustion, and an innovative CAR-T cell engineering approach is proposed to enhance CAR-T cell resilience against exhaustion.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shum, T. et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 7, 1238–1247 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nair, S. et al. Functional improvement of chimeric antigen receptor through intrinsic interleukin-15Rα signaling. Curr. Gene Ther. 19, 40–53 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y. G. et al. Modulation of BCL-2 in both T cells and tumor cells to enhance chimeric antigen receptor T-cell immunotherapy against cancer. Cancer Discov. 12, 2372–2391 (2022). The significance of this research lies in emphasizing the involvement of BCL-2 in tumour resistance to CAR-T cell immunotherapy, as well as introducing an innovative combination therapy. Specifically, it proposes the genetic engineering of CAR-T cells to withstand pro-apoptotic small molecules, thereby amplifying the effectiveness of these combined treatment approaches while avoiding the death of CAR-T cells.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Korell, F. et al. Chimeric antigen receptor (CAR) T cells overexpressing Bcl-xL increase proliferation and antitumor activity alone and in combination with BH3 mimetics. Cancer Res. 83, 4098 (2023).

    Article  Google Scholar 

  • Yamamoto, T. N. et al. T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. J. Clin. Invest. 129, 1551–1565 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Oda, S. K. et al. A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy. J. Exp. Med. 217, e20161166 (2020).

    Article  Google Scholar 

  • Shifrut, E. et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 175, 1958–1971.e15 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Carnevale, J. et al. RASA2 ablation in T cells boosts antigen sensitivity and long-term function. Nature 609, 174–182 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).

    Article  CAS  PubMed  Google Scholar 

  • Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  • Serganova, I. et al. Enhancement of PSMA-directed CAR adoptive immunotherapy by PD-1/PD-L1 blockade. Mol. Ther. Oncolytics 4, 41–54 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Fedorov, V. D., Themeli, M. & Sadelain, M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl Med. 5, 215ra172 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  • Li, A. M. et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Blood 132, 556 (2018).

    Article  Google Scholar 

  • Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  • Gumber, D. & Wang, L. D. Improving CAR-T immunotherapy: overcoming the challenges of T cell exhaustion. EBioMedicine 77, 103941 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yin, Y. et al. Checkpoint blockade reverses anergy in IL-13Rα2 humanized scFv-based CAR T cells to treat murine and canine gliomas. Mol. Ther. Oncolytics 11, 20–38 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Li, S. et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin. Cancer Res. 23, 6982–6992 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu, H. et al. CD19-specific CAR T cells that express a PD-1/CD28 chimeric switch-receptor are effective in patients with PD-L1-positive B-cell lymphoma. Clin. Cancer Res. 27, 473–484 (2021).

    Article  PubMed  Google Scholar 

  • Lee, Y. H. et al. PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells. Mol. Ther. 30, 579–592 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Dubovsky, J. A. et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122, 2539–2549 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang, M. L. et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 369, 507–516 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Byrd, J. C. et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 369, 32–42 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Long, M. et al. Ibrutinib treatment improves T cell number and function in CLL patients. J. Clin. Invest. 127, 3052–3064 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  • Fraietta, J. A. et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127, 1117–1127 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ruella, M. et al. The addition of the BTK inhibitor ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clin. Cancer Res. 22, 2684–2696 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Gill, S. I. et al. Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv. 6, 5774–5785 (2022). Together with Fraietta et al. (2016) and Ruella et al. (2016), this paper describes the combination of CAR-T cell therapy with the small-molecule BTK inhibitor ibrutinib, which leads to higher T cell viability and engraftment, suggesting the potential for improved outcomes in CLL and in patients with mantle cell lymphoma who are undergoing CAR-T cell therapy.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frey, N. V. et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J. Clin. Oncol. 38, 2862–2871 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frey, N. V. et al. Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J. Clin. Oncol. 38, 415–422 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Gauthier, J. et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood 132, 299 (2018).

    Article  Google Scholar 

  • Weber, E. W. et al. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 3, 711–717 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mestermann, K. et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl Med. 11, eaau5907 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Weber, E. W. et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 372, eaba1786 (2021). This article shows that continuous CAR stimulation induces profound functional, transcriptional and epigenetic changes in CAR-T cells. Owing to the reversible nature of epigenetic modifications leading to CAR-T cell exhaustion, the authors propose to reverse the process by intermittent blockade of CAR signalling using dasatinib.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Caforio, M. et al. PI3K/Akt pathway: the indestructible role of a vintage target as a support to the most recent immunotherapeutic approaches. Cancers 13, 4040 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klebanoff, C. A. et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight 2, e95103 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  • Alsina, M. et al. Updated results from the phase I CRB-402 study of anti-BCMA CAR-T cell therapy bb21217 in patients with relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes. Blood 136, 25–26 (2020).

    Article  Google Scholar 

  • Perkins, M. R. et al. Manufacturing an enhanced CAR T cell product by inhibition of the PI3K/Akt pathway during T cell expansion results in improved in vivo efficacy of anti-BCMA CAR T cells. Blood 126, 1893 (2015).

    Article  Google Scholar 

  • Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leen, A. M. et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121, 5113–5123 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • O’Reilly, R. J., Prockop, S., Hasan, A. N., Koehne, G. & Doubrovina, E. Virus-specific T-cell banks for ‘off the shelf’ adoptive therapy of refractory infections. Bone Marrow Transpl. 51, 1163–1172 (2016).

    Article  Google Scholar 

  • Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017). The TRAC locus has been extensively studied as an ideal target for both gene knockout and CAR knock-in. In this study, the authors used CRISPR–Cas9 to integrate a CD19-specific CAR coding sequence into the TRAC locus, aiming to eliminate existing TCRs while introducing the CD19-specific CAR in a manner that allows it to be regulated by the natural TCR promoter. This genetic modification unexpectedly led to several advantageous outcomes, including enhanced T cell functionality and improved control of pre-B-ALL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • MacLeod, D. T. et al. Integration of a CD19 CAR into the TCRα chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol. Ther. 25, 949–961 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sheridan, C. Off-the-shelf, gene-edited CAR-T cells forge ahead, despite safety scare. Nat. Biotechnol. 40, 5–8 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Benjamin, R. et al. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol. 9, e833–e843 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Benjamin, R. et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet 396, 1885–1894 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Mo, F. et al. Engineered off-the-shelf therapeutic T cells resist host immune rejection. Nat. Biotechnol. 39, 56–63 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Poirot, L. et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Valton, J. et al. A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol. Ther. 23, 1507–1518 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Graham, C., Jozwik, A., Pepper, A. & Benjamin, R. Allogeneic CAR-T cells: more than ease of access? Cells 7, 155 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nitsche, A. et al. Cytokine profiles of cord and adult blood leukocytes: differences in expression are due to differences in expression and activation of transcription factors. BMC Immunol. 8, 18 (2007).

    Article  PubMed Central  PubMed  Google Scholar 

  • Gutman, J. A. et al. Chronic graft versus host disease burden and late transplant complications are lower following adult double cord blood versus matched unrelated donor peripheral blood transplantation. Bone Marrow Transpl. 51, 1588–1593 (2016).

    Article  CAS  Google Scholar 

  • Sharma, P. et al. Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant. Blood Adv. 4, 2227–2235 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  • Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Khawar, M. B. & Sun, H. CAR-NK cells: from natural basis to design for kill. Front. Immunol. 12, 707542 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pan, K. et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J. Exp. Clin. Cancer Res. 41, 119 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu, Y. et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J. Hematol. Oncol. 12, 49 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Zhang, L., Meng, Y., Feng, X. & Han, Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark. Res. 10, 12 (2022).

    Article  PubMed Central  PubMed  Google Scholar 

  • Vahidian, F. et al. The tricks for fighting against cancer using CAR NK cells: a review. Mol. Cell Probes 63, 101817 (2022).

    Article  CAS  Google Scholar 

  • Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu, E. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520–531 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Matsubara, H., Niwa, A., Nakahata, T. & Saito, M. K. Induction of human pluripotent stem cell-derived natural killer cells for immunotherapy under chemically defined conditions. Biochem. Biophys. Res. Commun. 515, 1–8 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Juillerat, A. et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci. Rep. 7, 39833 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Daher, M. et al. The TGF-β/SMAD signaling pathway as a mediator of NK cell dysfunction and immune evasion in myelodysplastic syndrome. Blood 130, 53 (2017).

    Google Scholar 

  • Daher, M. et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 137, 624–636 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rodriguez-Garcia, A., Palazon, A., Noguera-Ortega, E., Powell, D. J. Jr & Guedan, S. CAR-T cells hit the tumor microenvironment: strategies to overcome tumor escape. Front. Immunol. 11, 1109 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Anderson, N. R., Minutolo, N. G., Gill, S. & Klichinsky, M. Macrophage-based approaches for cancer immunotherapy. Cancer Res. 81, 1201–1208 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Morrissey, M. A. et al. Chimeric antigen receptors that trigger phagocytosis. eLife 7, e36688 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  • Maude, S. L. et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. J. Clin. Oncol. 34, 3011 (2016).

    Article  Google Scholar 

  • Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee, D. W.III et al. Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood 128, 218 (2016).

    Article  Google Scholar 

  • Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372–385 (2019).

    CAS  PubMed Central  PubMed  Google Scholar 

  • Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Ruella, M. & Maus, M. V. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput. Struct. Biotechnol. J. 14, 357–362 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Spiegel, J. Y. et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat. Med. 27, 1419–1431 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Plaks V, C. J. et al. Axicabtagene ciloleucel (axi-cel) product attributes and immune biomarkers associated with clinical outcomes in patients (pts) with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5. Cancer Res. 81, CT036 (2021).

    Article  Google Scholar 

  • Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015). This report describes a novel mechanism for antigen-negative escape after CAR-T cell therapy. It provides a characterization of frameshift mutations occurring in exons 2 and 4 of the CD19 gene and of alternative spliced CD19 mRNA variants. These findings are based on the analysis of the initial four patients with B-ALL who participated in a clinical trial conducted at the Children’s Hospital of Philadelphia. Remarkably, the study demonstrates that anti-CD19 CAR-T cell therapy exerts selective pressure on cells, leading to pre-existing alternatively spliced CD19 isoforms that compromise the efficacy of CAR-T cell treatment.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fischer, J. et al. CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis. J. Immunother. 40, 187–195 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bagashev, A. et al. CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol. Cell. Biol. 38, e00383 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rabilloud, T. et al. Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy. Nat. Commun. 12, 865 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang, Z. et al. Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy. J. Immunother. Cancer 8, e001150 (2020).

    Article  PubMed Central  PubMed  Google Scholar 

  • Braig, F. et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood 129, 100–104 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Heard, A. et al. Antigen glycosylation regulates efficacy of CAR T cells targeting CD19. Nat. Commun. 13, 3367 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jacoby, E. et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wei, J. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13, 483–495 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shah, N. N. et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. J. Clin. Oncol. 38, 1938–1950 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Singh, N. et al. Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells. Nat. Med. 27, 842–850 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baird, J. H. et al. CD22-directed CAR T-cell therapy mediates durable complete responses in adults with relapsed or refractory large B-cell lymphoma after failure of CD19-directed CAR T-cell therapy and high response rates in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. Blood 136, 28–29 (2020).

    Article  Google Scholar 

  • Frank, J. M. et al. CD22 CAR T cell therapy induces durable remissions in patients with large B cell lymphoma who relapse after CD19 CAR T cell therapy. Presented at Tandem Meetings (2023).

  • Davenport, A. J. et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc. Natl Acad. Sci. USA 115, E2068–E2076 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xiong, W. et al. Immunological synapse predicts effectiveness of chimeric antigen receptor cells. Mol. Ther. 26, 963–975 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jeyakumar, N. et al. CD22 CAR T cells demonstrate favorable safety profile and high response rates in pediatric and adult B-ALL: results of a phase 1b study. Blood 140, 2374–2375 (2022).

    Article  Google Scholar 

  • Ali, S. A. et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cohen, A. D. et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J. Clin. Invest. 129, 2210–2221 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Gazeau, N. et al. Effective anti-BCMA retreatment in multiple myeloma. Blood Adv. 5, 3016–3020 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Green, D. J. et al. Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood 132, 1011 (2018).

    Article  Google Scholar 

  • Brudno, J. N. et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Timmers, M. et al. Chimeric antigen receptor-modified T cell therapy in multiple myeloma: beyond B cell maturation antigen. Front. Immunol. 10, 1613 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Singh, N. et al. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction. Cancer Discov. 10, 552–567 (2020). This study analyses the primary non-response to CAR-T cell therapy, which affects around 10–20% of patients and lacks a complete understanding of its underlying causes, and shows a reduced expression of cell-surface death receptors as an important inherited tumour-intrinsic factor leading to a lack of response to CAR-T cell therapy in ALL.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Masih KE, G. R. et al. Multi-omic analysis identifies mechanisms of resistance to CD19 CAR T-cell therapy in children with acute lymphoblastic leukemia. Cancer Res. 82, 3581 (2022).

    Article  Google Scholar 

  • Upadhyay, R. et al. A critical role for Fas-mediated off-target tumor killing in T-cell immunotherapy. Cancer Discov. 11, 599–613 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Lemoine, J., Ruella, M. & Houot, R. Overcoming intrinsic resistance of cancer cells to CAR T-cell killing. Clin. Cancer Res. 27, 6298–6306 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Young, R. M., Engel, N. W., Uslu, U., Wellhausen, N. & June, C. H. Next-generation CAR T-cell therapies. Cancer Discov. 12, 1625–1633 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frey, N. V. et al. CART22-65s co-administered with huCART19 in adult patients with relapsed or refractory all. Blood 138, 469 (2021).

    Article  Google Scholar 

  • Wang, T. et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J. Clin. Oncol. 41, 1670–1683 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Wang, T. et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J. Clin. Oncol. 20, 1670–1683 (2022).

    Google Scholar 

  • Kokalaki, E. et al. Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR. Mol. Ther. 31, 2089–2104 (2023).

    Article  CAS  PubMed  Google Scholar 

  • Cordoba, S. et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat. Med. 27, 1797–1805 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gardner, R. et al. Early clinical experience of CD19 × CD22 dual specific CAR T cells for enhanced anti-leukemic targeting of acute lymphoblastic leukemia. Blood 132, 278 (2018).

    Article  Google Scholar 

  • Wang, N. et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood 135, 17–27 (2020).

    Article  PubMed  Google Scholar 

  • Roddie, C. et al. Dual targeting of CD19 and CD22 with bicistronic CAR-T cells in patients with relapsed/refractory large B cell lymphoma. Blood 141, 2470–2482 (2023).

    CAS  PubMed  Google Scholar 

  • Fousek, K. et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia 35, 75–89 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Qin, H. et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther. Oncolytics 11, 127–137 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shalabi, H. et al. CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR. Blood 140, 451–463 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shah, N. N. et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat. Med. 26, 1569–1575 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. 126, 3814–3826 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  • Hu, B. et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kueberuwa, G., Kalaitsidou, M., Cheadle, E., Hawkins, R. E. & Gilham, D. E. CD19 CAR T cells expressing IL-12 eradicate lymphoma in fully lymphoreplete mice through induction of host immunity. Mol. Ther. Oncolytics 8, 41–51 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Shalabi, H. et al. Case report: impact of BITE on CAR-T cell expansion. Adv. Cell Gene Ther. 2, e50 (2019).

    Article  Google Scholar 

  • Laurent, S. A. et al. γ-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat. Commun. 6, 7333 (2015).

    Article  CAS  PubMed  Google Scholar 

  • Pont, M. J. et al. γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood 134, 1585–1597 (2019).

    Article  PubMed Central  PubMed  Google Scholar 

  • Yan, Z. et al. A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial. Lancet Haematol. 6, e521–e529 (2019).

    Article  PubMed  Google Scholar 

  • Tang, F., Lu, Y., Ge, Y., Shang, J. & Zhu, X. Infusion of chimeric antigen receptor T cells against dual targets of CD19 and B-cell maturation antigen for the treatment of refractory multiple myeloma. J. Int. Med. Res. 48, 300060519893496 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Majzner, R. G. et al. Tuning the antigen density requirement for CAR T-cell activity. Cancer Discov. 10, 702–723 (2020). This study finds extensive interpatient and intrapatient heterogeneity in tumour expression of CAR-T cell target antigens, including CD19. An analysis of the immunological synapse revealed that CD28 H/T domain-expressing CAR-T cells were more efficient at recognizing low-density antigens and forming clusters to induce T cell activation. This research illustrates the adjustable nature of the sensitivity of CAR-T cells to the density of antigens on target cells, paving the way for exploring novel approaches in the development of CAR-based therapies.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dourthe, M. E. et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia 35, 3383–3393 (2021).

    Article  CAS  PubMed  Google Scholar 

  • Kankeu Fonkoua, L. A., Sirpilla, O., Sakemura, R., Siegler, E. L. & Kenderian, S. S. CAR T cell therapy and the tumor microenvironment: current challenges and opportunities. Mol. Ther. Oncolytics 25, 69–77 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Srivastava, S. & Riddell, S. R. Chimeric antigen receptor T cell therapy: challenges to bench-to-bedside efficacy. J. Immunol. 200, 459–468 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Jain, M. D. et al. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma. Blood 137, 2621–2633 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boulch, M. et al. A cross-talk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity. Sci. Immunol. 6, eabd4644 (2021).

    Article  Google Scholar 

  • Gato-Canas, M. et al. PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity. Cell Rep. 20, 1818–1829 (2017).

    Article  CAS  PubMed  Google Scholar 

  • Spranger, S. et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci. Transl Med. 5, 200ra116 (2013).

    Article  PubMed Central  PubMed  Google Scholar 

  • Bailey, S. R. et al. Blockade or deletion of IFNγ reduces macrophage activation without compromising CAR T-cell function in hematologic malignancies. Blood Cancer Discov. 3, 136–153 (2022). This study shows that blocking or genetically removing IFNγ from CAR-T cells does not hinder their antitumour efficacy. Interestingly, this approach leads to a reduced expression of immune checkpoint receptors on CAR-T cells and less activation of macrophages. These findings suggest the potential for separating the toxic side effects from the therapeutic efficacy of CAR-T cells, offering the possibility of safer yet still effective use of this therapy.

    Article  PubMed Central  PubMed  Google Scholar 

  • Larson, R. C. et al. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours. Nature 604, 563–570 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Scholler, N. et al. Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat. Med. 28, 1872–1882 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).

    Article  CAS  PubMed  Google Scholar 

  • Cioroianu, A. I. et al. Tumor microenvironment in diffuse large B-cell lymphoma: role and prognosis. Anal. Cell. Pathol. 2019, 8586354 (2019).

    Article  Google Scholar 

  • Simioni, C. et al. The complexity of the tumor microenvironment and its role in acute lymphoblastic leukemia: implications for therapies. Front. Oncol. 11, 673506 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garcia-Ortiz, A. et al. The role of tumor microenvironment in multiple myeloma development and progression. Cancers 13, 217 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yan, Z. X. et al. Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin’s lymphoma. Clin. Cancer Res. 25, 6995–7003 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Perna, S. K. et al. Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. Clin. Cancer Res. 20, 131–139 (2014).

    Article  CAS  PubMed  Google Scholar 

  • Chen, Y. et al. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin. Cancer Res. 25, 2915–2924 (2019).

    Article  CAS  PubMed  Google Scholar 

  • Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130–2141 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang, Z., Miao, L., Ren, Z., Tang, F. & Li, Y. Gene-edited interleukin CAR-T cells therapy in the treatment of malignancies: present and future. Front. Immunol. 12, 718686 (2021).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Koneru, M., Purdon, T. J., Spriggs, D., Koneru, S. & Brentjens, R. J. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).

    Article  PubMed Central  PubMed  Google Scholar 

  • Gardner, T. J. et al. Engineering CAR-T cells to activate small-molecule drugs in situ. Nat. Chem. Biol. 18, 216–225 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Kofler, D. M. et al. CD28 costimulation impairs the efficacy of a redirected T-cell antitumor attack in the presence of regulatory T cells which can be overcome by preventing Lck activation. Mol. Ther. 19, 760–767 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sadeghalvad, M., Mohammadi-Motlagh, H.-R. & Rezaei, N. in Encyclopedia of Infection and Immunity (ed. Nima, R.) 130–143 (Elsevier, 2022).

  • Nouri, Y., Weinkove, R. & Perret, R. T-cell intrinsic Toll-like receptor signaling: implications for cancer immunotherapy and CAR T-cells. J. Immunother. Cancer 9, e003065 (2021).

    Article  PubMed Central  PubMed  Google Scholar 

  • Ruella, M. et al. Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells. Cancer Discov. 7, 1154–1167 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith, M. et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat. Med. 28, 713–723 (2022). This article analyses the role of faecal microbiota composition of patients receiving second-generation anti-CD19 CAR-T cell therapy for the treatment of B cell malignancies. The exposure of patients to broad-spectrum antibiotics correlated with worse overall survival and progression-free survival and a greater incidence of immune effector cell-associated neurotoxicity syndrome. In addition, the presence of certain microbial taxa, specifically the class Clostridia, was associated with higher rates of complete response following CAR-T cell infusion, whereas Bacteroides was associated with toxicity. Therefore, antibiotic exposure, which can alter the gut microbiota, before CAR-T cell therapy is probably contributing to its antitumour effectiveness and toxicity.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stein-Thoeringer, C. K. et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat. Med. 29, 906–916 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Siddiqi, T. et al. Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood 139, 1794–1806 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Minson, A. et al. A phase II, open-label, single arm trial to assess the efficacy and safety of the combination of tisagenlecleucel and ibrutinib in mantle cell lymphoma (TARMAC). Blood 136, 34–35 (2020).

    Article  Google Scholar 

  • Tong, C. et al. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma. Blood 136, 1632–1644 (2020).

    PubMed Central  PubMed  Google Scholar 

  • Zhang, Y. et al. Long-term activity of tandem CD19/CD20 CAR therapy in refractory/relapsed B-cell lymphoma: a single-arm, phase 1-2 trial. Leukemia 36, 189–196 (2022).

    Article  CAS  PubMed  Google Scholar 

  • Sang, W. et al. Phase II trial of co-administration of CD19- and CD20-targeted chimeric antigen receptor T cells for relapsed and refractory diffuse large B cell lymphoma. Cancer Med. 9, 5827–5838 (2020).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Larson, S. M. et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma. Cancer Discov. 13, 580–597 (2023).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cowan, A. J. et al. Efficacy and safety of fully human BCMA CAR T cells in combination with a gamma secretase inhibitor to increase BCMA surface expression in patients with relapsed or refractory multiple myeloma. Blood 134, 204 (2019).

    Article  Google Scholar 

  • Du, J. et al. Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 40, 8005 (2022).

    Article  Google Scholar 

  • Grover, N. S. et al. CD30-directed CAR-T cells co-expressing CCR4 in relapsed/refractory Hodgkin lymphoma and CD30+ cutaneous T cell lymphoma. Blood 138, 742 (2021).

    Article  Google Scholar 

  • Narayan, V. et al. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sources


    Article information

    Author: Victoria Johnson

    Last Updated: 1700158681

    Views: 1409

    Rating: 3.6 / 5 (103 voted)

    Reviews: 85% of readers found this page helpful

    Author information

    Name: Victoria Johnson

    Birthday: 1964-07-30

    Address: 9620 Rivera Brooks Suite 465, North Kent, IL 99164

    Phone: +3684494089124663

    Job: Carpenter

    Hobby: Amateur Radio, Role-Playing Games, Golf, Wine Tasting, Basketball, Stargazing, Scuba Diving

    Introduction: My name is Victoria Johnson, I am a resolute, treasured, resolved, honest, talented, dedicated, accessible person who loves writing and wants to share my knowledge and understanding with you.