Here, we highlight key papers published in 2018 that advance our understanding of resistance to chimeric antigen receptor (CAR) T cell immunotherapy for leukaemia and lymphoma and in so doing reveal barriers that must be addressed to increase efficacy of this novel class of therapeutics for B cell malignancies and expand their reach to solid tumours.
CD19-targeted chimeric antigen receptor (CAR) T cells induce high complete response rates in paediatric B cell acute lymphoblastic leukaemia (B-ALL) cases, but many of these patients will relapse, most often with CD19-negative leukaemia.
CD22-directed CAR T cells induce high response rates in CD19-naive or CD19-resistant B-ALL, but often relapse with CD22lo leukaemia.
Intrinsic gene programmes of memory versus exhaustion correlate with T cell fitness and determine response to CD19-targeted CAR T cells in chronic lymphocytic leukaemia (CLL).
Loss of Tet methylcytosine dioxygenase 2 (TET2), an epigenetic modulator, prevented terminal T cell differentiation and enabled the progeny of a single CD8+ CAR T cell clone to mediate complete remission in a patient with CLL.
After decades of research, immunotherapy is advancing the care of cancer patients at an unprecedented pace. Chimeric antigen receptor (CAR) T cell immunotherapy was named the “advance of the year” in 2018 by the American Society of Clinical Oncology (ASCO) following FDA approval of CD19-targeted CAR T cells for adult and paediatric patients with certain refractory B cell malignancies.
The first cell therapy approved for the treatment of cancer and the first gene therapy approved in the United States, CAR T cell therapy has evolved from a boutique approach under study in a handful of academic centres to a commercialized immunotherapy that is now being integrated into standard cancer care. Following this success, arguably the major question facing this field is whether the impact of CAR T cells will remain limited to a relatively restricted group of patients with B cell malignancies or expand to other haematological cancers and solid tumours. Here we highlight some of the scientific advances in 2018 that have begun to define major mechanisms of resistance to CAR T cell therapy in B cell malignancies and thereby identify the challenges that need to be addressed if these agents are to find broader application.
Clinical results from the pivotal phase II trial of the CD19-targeted CAR T cell therapy tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukaemia (B-ALL)1 demonstrated an 81% complete response (CR) rate at 28 days following infusion, although relapse-free survival was 59% with a relatively short median follow-up duration of 12 months. Among 16 patients for whom the cause of relapse was assessed in this study, 94% resulted from antigen loss, which occurs most commonly as a result of genetic mutation and/or enrichment of CD19 variants expressing isoforms that lack the transmembrane domain or targeted exon2,3,4. These results identify acquired resistance due to emergence of CD19 variants as a major barrier to success of CD19-targeted CAR T cell therapy for B-ALL. Results of the pivotal phase II trial of the CD19-directed CAR T cell therapy axicabtagene ciloleucel in refractory large B cell lymphoma were also recently reported5 and demonstrated CR in 54% of patients receiving the therapy, confirming a lower CR rate in this disease than that seen in B-ALL. Notably, however, CRs in lymphoma were highly durable, with only 14% of patients experiencing relapse (median follow-up 15.4 months), of which 27% was attributed to antigen loss5. The mechanism of CD19 loss in lymphoma has not been characterized.
The emergence of antigen loss in both B-ALL and large B cell lymphoma following CD19-targeted CAR T cell therapy has fuelled the development of CARs targeting alternative B cell antigens. This year, Fry and colleagues6 published the results of a trial of CD22-targeted CAR T cells in 21 paediatric B-ALL patients, reporting a 73% CR rate for patients who received >1 × 106 cells, similar to CR rates observed following CD19-targeted CAR T cells. Prior CAR therapy did not impact responses as five of five patients who had relapsed following CD19-directed immunotherapy with CD19low or CD19– disease achieved a CR with CD22-targeted CAR T cell therapy, suggesting that inherent resistance to immunotherapy is not a major factor in disease recurrence. This study, along with phase I data reported this year for B cell maturation antigen (BCMA)-targeted CAR T cells for the treatment of multiple myeloma7, lends support to the notion that potent CAR T cells can be generated against numerous cell surface targets and that CD19 is not unique in this regard.
The study by Fry et al.6 also highlighted antigen escape as a mechanism of acquired resistance, but, rather than antigen loss, relapse following CD22-targeted CAR T cell therapy was typically associated with modestly diminished expression of CD22, which was apparently sufficient to evade detection by CD22-targeted CAR T cells. Emergence of antigen-negative and antigen-low escape has incentivized several groups to attempt to ‘box in’ tumours using multi-antigen-targeted CAR T cells. With this in mind, Fry et al.6 developed a bispecific CD19/CD22-targeted CAR T cell product and demonstrated its ability to redirect T cell activity against two independent cell surface molecules. We anticipate that multispecific CAR T cells will become increasingly important as the community seeks to enhance the efficacy of CAR T cells against acute myelogenous leukaemia and solid tumours, which demonstrate high levels of interpatient and intrapatient heterogeneity in surface antigen expression.
Several papers in 2018 also elucidated the importance of the intrinsic fitness of the T cell as a critical differentiator between responding and non-responding patients8,9,10. Fraietta and colleagues8 examined determinants of response and resistance for 41 patients with advanced, high-risk chronic lymphocytic leukaemia (CLL). Intrinsic properties of T cells within the CD19-targeted CAR T cell product were the most important variables associated with clinical response and eclipsed the impact of disease and/or patient-related differences, including age, cancer subtype or disease burden. CD19-targeted CAR T cells within manufactured products from responding patients showed enhanced transcription of genes associated with memory T cells, had greater ex vivo proliferative potential and had a more robust increase in the transcription of genes associated with activation following antigen stimulation. In this study, CAR T cell products from responding patients also displayed an upregulation of the IL-6–STAT3 pathway, potentially implicating STAT3 in enhanced functionality and long-term persistence. By contrast, CAR T cells from non-responders exhibited an increased expression of gene programmes involved in T cell effector functions and exhaustion and a higher uptake of glucose. Examination of the T cell subsets associated with a clinical response identified an increased frequency of CD27+CD45RO−CD8+ T cells used for manufacture and CD27+PD1−CD8+ CAR T cells in the infusion product as correlated with therapeutic activity.
This study provides compelling evidence that predictive biomarkers can identify CAR T cell products with a greater likelihood of mediating therapeutic activity. Approaches to engineer T cells with an enhanced capacity for memory self-renewal and a diminished propensity for exhaustion are under intense investigation, and an extraordinary case study reported by Fraietta and colleagues9 provides a glimpse into the transformative potential of such strategies. This study demonstrated that progeny from a single CD8+ CAR T cell clone, which had a disruption in the Tet methylcytosine dioxygenase 2 (TET2) gene, mediated complete remission in a CLL patient. Why was this CAR T cell clone so therapeutically effective? The authors demonstrate that serendipitous integration of the CAR transgene into the TET2 locus resulted in TET2 loss-of-function (the patient also had an underlying TET2 hypomorphic missense mutation), which globally altered chromatin methylation patterns, reduced T cell differentiation and led to clonal expansion of clinically potent memory T cells. Indeed, at the peak of in vivo CAR T cell expansion, more than 65% of the cells exhibited a central memory phenotype. Taken together, these studies support the generalizable theme that CAR T cell products can be engineered to mediate enhanced functionality by maintaining a less-differentiated phenotype and thereby avoid conditions that promote T cell exhaustion.
Overall, studies in 2018 confirmed that the major barriers to progress in the development of CAR T cell products relate to antigen escape and intrinsic T cell dysfunction (Fig. 1). Antigen escape can occur by either loss of the targeted epitope or selection of antigen-low variants that evade detection by CAR T cells. T cell failure is associated with T cell exhaustion, and disruption of the TET2 locus may be sufficient to endow T cells with resistance to such dysfunction. We look forward to advances in CAR T cell engineering that will address these challenges and increase the likelihood that the impact of this novel class of therapeutics will expand beyond the reach of B cell malignancies.
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
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).
Bagashev, A. et al. CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol. Cell Biol. https://doi.org/10.1128/MCB.00383-18 (2018).
Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).
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).
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).
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).
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).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
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).
C.L.M. and C.B. are members of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University and City of Hope Cancer Immunotherapy Program.
C.L.M. is a member of the Scientific Advisory board and/or has provided consulting services for Adaptimmune LLC, Allogene, Apricity Health, GlaxoSmithKline Cell and Gene Therapy, Lyell Immunopharma, Nektar, PACT Pharma, Pfizer, Roche, TPG, Unum Therapeutics and Vor Pharmaceuticals. C.L.M. owns equity in Apricity Health, Lyell Immunopharma, PACT Pharma, Unum Therapeutics and Vor Pharmaceuticals and has received research funding from Bluebird Bio and Obsidian Therapeutics. C.B. declares no competing interests.
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Brown, C.E., Mackall, C.L. CAR T cell therapy: inroads to response and resistance. Nat Rev Immunol 19, 73–74 (2019). https://doi.org/10.1038/s41577-018-0119-y
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