Late Events After CD-19 CAR-T Treatment

Conventional therapy for patients with relapsed/refractory CD19+ lymphomas and leukemias has unacceptably low long-term progression-free survival. Enthusiasm for using CD19 chimeric antigen receptor (CAR) T cell therapy for treating these patients is based on the impressive results in patients with Acute B Lymphoblastic Leukemia (complete response CR rates ≥70% in multiple trials) and Diffuse Large B-cell Lymphoma (DLBCL) (82% response rate/54% CR rate) 1Maude S.L. Laetsch T.W. Buechner J. et al.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med. 2018; 378: 439-448Crossref PubMed Scopus (1676) Google Scholar,2Neelapu S.S. Locke F.L. Bartlett N.L. et al.Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma.N Engl J Med. 2017; 377: 2531-2544Crossref PubMed Scopus (1726) Google Scholar. These results have led to Food and Drug Administration approval for tisagenlecleucel (Novartis, Basel, Switzerland) for pediatric acute lymphoblastic leukemia (ALL) and adult DLBCL patients and axicabtagene ciloleucel (Kite-Gilead, Los Angeles, USA) for adults with DLBCL. A great deal of attention has been paid to the acute toxicities of CD19 CAR T cell therapy—namely, cytokine release syndrome and Immune Effector Cell-associated neurotoxicity syndrome, including their identification, grading, and management 3Lee D.W. Santomasso B.D. Locke F.L. et al.ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.Biol Blood Marrow Transplant. 2019; 25: 625-638Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar,4Santomasso B. Bachier C. Westin J. Rezvani K. Shpall E.J. The other side of CAR T-cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden.Am Soc Clin Oncol Educ Book. 2019; 39: 433-444Crossref PubMed Google Scholar. However, as experience with CD19-directed T cell therapy has grown, there is an increased awareness of the long-term adverse events. The article by Cordeiro et al. 5Cordeiro A. Bezerra E.D. Hirayama A.V. et al.Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells.Biol Blood Marrow Transplant. 2020; 26: 26-33Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar fills an important gap in the literature by reporting on long-term adverse events in a cohort of patients with a variety of B cell malignancies (ALL, non-Hodgkin lymphoma, or chronic lymphocytic leukemia) treated with CD19 CAR T cells in a single-site phase I/II study (NCT01865617). The authors limited their analysis to a cohort of patients who survived at least a year after receiving CAR T cell therapy and excluded all patients who had subsequent lines of therapy, including allogeneic stem cell transplant. They defined long-term adverse events as complications developing after or persisting beyond day 90 following CAR infusion. Their analysis found that 16% of patients with ongoing CR had prolonged cytopenias lasting 15.2 to 21.7 months compared with 0% in the non-CR group. The cumulative incidence of hypogammaglobulinemia (HGG) was 74% in the CR group and 61% in the non-CR group. Late infections where reported for 54 patients, 23 with multiple infections. The rate of secondary malignancies was 15%, including 6 nonmelanoma skin cancers, 4 myelodysplastic syndromes, 1 melanoma, 1 noninvasive bladder cancer, and 1 multiple myeloma. The authors reported an 8% rate of immune-related events, categorized as lymphocytic alveolitis, skin rash, eosinophilic pneumonia, pneumonitis not otherwise specified, granulomatous disease not otherwise specified, persistent flu-like syndrome, and collagenous colitis. Graft-versus-host disease (GVHD) was reported in 3 patients (out of a total 15 who had previous allogeneic stem cell transplant before CAR infusion), all of whom were in CR. Neurologic and psychiatric events were reported in 10% of patients (n = 9), including 3 cerebrovascular accidents, 1 transient ischemic attack, Alzheimer dementia and peripheral neuropathy (2 patients developed both entities), and 8 patients with psychiatric events (4 newly diagnosed and 4 with exacerbation of previously known psychiatric diagnoses). During the longitudinal care of CAR T cell patients, it is of great importance that clinicians increase their awareness of the long-term complications associated with CD19 CAR T cells. Most physicians experienced in treating patients with hematologic malignancies often encounter treatment-related cytopenias, HGG, persistent infections, secondary malignancies, immune-related phenomenon, and GVHD. However, the neurologic/psychiatric issues that can arise months to years after CAR T cell therapy are a concern. Currently, no guidelines exist to assist clinicians in the long-term care of CAR T cell patients, whether it is the surveillance plan for future malignancies/immune-related events/GVHD, the optimal management of persistent cytopenias/HGG, or how to screen for and address late-onset neurologic/psychiatrics issues. In the absence of committee-based guidelines, developing institutional practices to optimize CD19 CAR T cell patient care is critical. Certain institutions, including ours, model the care plan for CD19 CAR T cell patients after the care plan for autologous stem cell transplant patients. All patients considered for CAR T cell therapy have psychologic evaluations before CAR T cell infusion and regular follow-up to monitor for emerging neurologic or psychiatric events. The real question is how the CD19 CAR T cell therapy can be improved to retain the high clinical response rates while limiting both short- and long-term adverse events 9Mata M. Gottschalk S. Engineering for success: approaches to improve chimeric antigen receptor T cell therapy for solid tumors.Drugs. 2019; 79: 401-415Crossref PubMed Scopus (10) Google Scholar. Therefore, it is best to consider the adverse events associated with the preparative chemotherapy regimen separately from the CD19 CAR T cell adverse events. There are reports in animal models of strategies to maintain T cell persistence following adoptive transfer without the need for lymphodepletion 6Johnson C.B. May B.R. Riesenberg B.P. et al.Enhanced lymphodepletion is insufficient to replace exogenous IL2 or IL15 therapy in augmenting the efficacy of adoptively transferred effector CD8(+) T cells.Cancer Res. 2018; 78: 3067-3074Crossref PubMed Scopus (2) Google Scholar,7Ng S.S.M. Nagy B.A. Jensen S.M. et al.Heterodimeric IL15 treatment enhances tumor infiltration, persistence, and effector functions of adoptively transferred tumor-specific T cells in the absence of lymphodepletion.Clin Cancer Res. 2017; 23: 2817-2830Crossref PubMed Scopus (18) Google Scholar. Such strategies, if proven to not reduce the efficacy of the CD19 CAR T cells, would reduce any long-term non-B cell cytopenias, potential for secondary bone marrow-related malignancies, and the overall cost of the CD19 CAR T therapy. However, most investigators in the field have focused on strategies to improve the safety of the CD19 CAR T cells themselves 8Perales M.A. Kebriaei P. Kean L.S. Sadelain M. Building a safer and faster CAR: seatbelts, airbags, and CRISPR.Biol Blood Marrow Transplant. 2018; 24: 27-31Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,9Mata M. Gottschalk S. Engineering for success: approaches to improve chimeric antigen receptor T cell therapy for solid tumors.Drugs. 2019; 79: 401-415Crossref PubMed Scopus (10) Google Scholar. There is clear evidence that the choice of CAR construct costimulatory cassette impacts the persistence and function of CAR T cells 10Priceman S.J. Gerdts E.A. Tilakawardane D. et al.Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.Oncoimmunology. 2018; 7e1380764Crossref PubMed Scopus (57) Google Scholar, 11Weinkove R. George P. Dasyam N. McLellan A.D. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations.Clin Transl Immunol. 2019; 8: e1049Crossref PubMed Scopus (87) Google Scholar, 12Quintarelli C. Orlando D. Boffa I. et al.Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma.Oncoimmunology. 2018; 7e1433518Crossref PubMed Scopus (54) Google Scholar. CD19 CAR T cell persistence is the likely culprit for many of the late-term adverse events reported by Cordeiro et al. 5Cordeiro A. Bezerra E.D. Hirayama A.V. et al.Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells.Biol Blood Marrow Transplant. 2020; 26: 26-33Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, especially the persistent HGG as well as the late onset of infections, immune-related events, and neurologic/psychiatric events. One solution to long-term T cell persistence would be including a suicide gene into the vector 13Budde L.E. Berger C. Lin Y. et al.Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma.PLoS One. 2013; 8: e82742Crossref PubMed Scopus (125) Google Scholar, 14Drent E. Poels R. Mulders M.J. et al.Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design.PLoS One. 2018; 13e0197349Crossref PubMed Scopus (26) Google Scholar, 15Hoyos V. Savoldo B. Quintarelli C. et al.Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.Leukemia. 2010; 24: 1160-1170Crossref PubMed Scopus (333) Google Scholar, 16Stavrou M. Philip B. Traynor-White C. et al.A rapamycin-activated caspase 9-based suicide gene.Mol Ther. 2018; 26: 1266-1276Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 17Wang X. Chang W.C. Wong C.W. et al.A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells.Blood. 2011; 118: 1255-1263Crossref PubMed Scopus (338) Google Scholar. However, early elimination of the CD19 CAR T cells could promote disease relapse. Alternatively, CAR constructs have been developed that require targeting more than CD19 alone to activate the CAR T cells, which should preserve normal B cells and eliminate HGG 18Roybal K.T. Rupp L.J. Morsut L. et al.Precision tumor recognition by t cells with combinatorial antigen-sensing circuits.Cell. 2016; 164: 770-779Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar,19Roybal K.T. Williams J.Z. Morsut L. et al.Engineering T cells with customized therapeutic response programs using synthetic Notch receptors.Cell. 2016; 167 (419-432.e416)Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar. Another promising approach is to use universal CAR T cells 20Minutolo N.G. Hollander E.E. Powell Jr., D.J. The emergence of universal immune receptor T cell therapy for cancer.Front Oncol. 2019; 9: 176Crossref PubMed Scopus (39) Google Scholar,21Rataj F. Jacobi S.J. Stoiber S. et al.High-affinity CD16-polymorphism and Fc-engineered antibodies enable activity of CD16-chimeric antigen receptor-modified T cells for cancer therapy.Br J Cancer. 2019; 120: 79-87Crossref PubMed Scopus (14) Google Scholar. Universal CAR T cells themselves persist long term but only function after they are loaded with a receptor/antibody in vivo. This single-site report by Cordeiro et al. 5Cordeiro A. Bezerra E.D. Hirayama A.V. et al.Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells.Biol Blood Marrow Transplant. 2020; 26: 26-33Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar raises concerns about critical late adverse events in CD19 CAR T cell patients, but solutions are on the horizon. Further investigation using a larger patient cohort and other clinical grade CD19 CAR construct use by other investigators is required to improve the safety of CD19 CAR T cell therapy.