Abstract
We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.
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Data availability
All requests for raw and analyzed data and materials are promptly reviewed by the University of Pennsylvania and the corresponding author, to determine whether they are subject to intellectual property or confidentiality obligations. Patient-related data not included in the paper may be subject to patient confidentiality. The email address for the corresponding author is mruella@upenn.edu. Any data and materials that can be shared will be released via a material transfer agreement.
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Acknowledgements
We thank all the patients and their families. We acknowledge the work of nurses and clinical research staff at the Hospital of the University of Pennsylvania. We acknowledge the laboratories and staff in the Division of Precision and Computational Diagnostics (Center for Personalized Diagnostics and Molecular Pathology Laboratory at Hospital of University of Pennsylvania) for performing additional NGS assays to support the study. This research was supported by the National Institutes of Health National Cancer Institute (P01 PCA214278C and R01/37-CA262362-01A1) to M.R., the Laffey McHugh Foundation (M.R. and J.S.), the Berman and Maguire Funds for Lymphoma Research at Penn (M.R. and S.J.S.), the SITC-Mallinckrodt Pharmaceuticals Adverse Events in Cancer Immunotherapy Clinical Fellowship (G.G., no grant number), the Mario Luvini Fellowship grant—Fondazione Ticinese per la Ricerca sul Cancro (G.G., no grant number) and the Leukemia and Lymphoma Society Scholar in Clinical Research award (A.L.G., grant 2329-20). E.A.C. was supported by an LRF Clinical Investigator Career Development Award.
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Contributions
G.G. and M.R. conceptualized the project, interpreted the results and drafted the manuscript. G.G., L.P., E.F., E.R.C. and V.P. collected the clinical data. G.G., L.P., O.H.U. and R.P. collected and processed the biospecimens. J.A.F. and I.K. performed CAR qPCR on biospecimens and interpreted the results. J.C.H. and G.C.C. evaluated histopathological samples, integrated morphological, immunophenotypical and genomic data, edited the manuscript and prepared pathology microphotographs. J.J.D.M., V.M.V. and D.B.L. performed, analyzed and interpreted sequencing analysis and TRG/IGH clonality analysis, respectively. J.N.G. managed the patients with TCL. E.A.C., S.P.S.A., J.S., S.D.N., D.J.L., A.J.W., A.D.C., E.A.S., N.V.F., D.T.V., E.O.H., S.K.B., D.L.P., A.L.G. and S.J.S. treated the other patients analyzed in the study. B.L.L. and C.H.J. reviewed, provided conceptual feedback and edited the manuscript. All authors reviewed and approved the manuscript.
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Competing interests
G.G. served as a scientific consultant for viTToria Biotherapeutics. M.R. holds patents related to CD19 CAR T cells, served as a consultant for NanoString, Bristol Myers Squibb, GlaxoSmithKline, Scaylite, Bayer and AbClon; and receives research funding from AbClon, NanoString, Oxford NanoImaging, viTToria Biotherapeutics, CURIOX and Beckman Coulter. M.R. is the scientific founder of viTToria Biotherapeutics. J.S. served as a consultant for Genmab, Adaptive, AstraZeneca, BMS, ADCT, Atara, Pharmacyclics and Seattle Genetics and received research funding from AstraZeneca, BMS, Incyte, Merck, Seattle Genetics, Pharmacyclics and TG Therapeutics. G.C.C. served as a consultant for DAVA Oncology and GLG consulting. E.A.C. served as a consultant for AstraZeneca, Novartis, Beigene, KITE and Juno/BMS and received research funding from Abbvie and Genentech/Roche. S.K.B. served as a consultant to Acrotech, Affimed, Kyowa Kirin, Daiichi Sankyo, Janssen and Seagen. S.D.N. received research funding from Pharmacyclics, Roche, Rafael and FortySeven/Gilead. J.D.L. received research funding from Curis, Takeda and Triphase and served on the Board of Directors, advisory committees and data and safety monitoring board for Incyte, ADCT, Karyopharm and Morphosis. S.J.S. served as a consultant to AstraZeneca, BeiGene, Celgene, Genentech, Genmab, Fate Therapeutics, Roche, Incyte, Juno Therapeutics, Legend Biotech, Loxo Oncology, MorphoSys, Mustang Biotech, Nordic Nanovector, Novartis and Regeneron; received research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech, Roche, Juno Therapeutics, Merck, Novartis, Incyte, Pharmacyclics and TG Therapeutics; received honoraria from Celgene and Novartis; and holds patents related to CD19 CAR T cells and autologous co-stimulated T cells. D.L.P. declares funding from the National Marrow Donor Program; membership on an entity’s Board of Directors or advisory committees of Kite/Gilead, Janssen, Genentech, DeCart, Sana Biotechnology, Verisimo and Novartis; is a current equity holder of the American Society for Transplantation and Cellular Therapy and Verismo; declares honoraria for Incyte; patents and royalties in Tmunity and Wiley and Sons Publishing. A.L.G. declares research support from Janssen, Novartis, Tmunity and CRISPR Therapeutics; consultancies/honoraria from Janssen, Novartis, BMS, GSK and Legend Bio; and DSMB membership for Janssen. C.H.J. and the University of Pennsylvania have patents pending or issued related to the use of gene modification in T cells for adoptive T cell therapy. C.H.J. is a co-founder of Tmunity, is a scientific co-founder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics and Bluewhale Bio. C.H.J. serves on the board of AC Immune and is a scientific advisor to BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Cellcarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite, Poseida, Verismo, Viracta, Vittoria Bio and WIRB-Copernicus group. C.H.J. is an inventor on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and Kite and may receive license revenue from such licenses. J.A.F. is a member of the Scientific Advisory Boards of Cartography Bio and Shennon Biotechnologies and has patents, royalties and other intellectual property. B.L.L. reports personal fees from Akron, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, Thermo Fisher Pharma Services, UTC Therapeutics and Vycellix and is a co-founder and equity holder in Tmunity Therapeutics (acquired by Kite Pharma) and Capstan Therapeutics. N.V.F. declares an affiliation with Sana Biotechnology; consultancy roles for Novartis and Syndax Pharmaceuticals; and research funding from Kite Pharma. E.A.S. declares an affiliation with Oncopeptides; consultancy for Amgen, BMS Celgene, G.S.K., Janssen and AbbVie. E.O.H. declares an affiliation with Tmunity Therapeutics and research funding from Blueprint Medicines and PharmaEssentia; membership on an entity′s Board of Directors or advisory committees for Blueprint Medicines and PharmaEssentia. D.T.V. has received research funding from Takeda and Active Biotech and consulting fees from Takeda, Karyopharm, GSK, Genentech and Sanofi. A.D.C. is a scientific advisor for Janssen and BMS and has received research support and royalties from Novartis. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Histopathological evaluation of the recurrent B cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma (‘grey zone’ lymphoma).
H&E staining and immunohistochemistry were performed for CD5, CD20, CD30, CD79a, and PAX5, highlighting B cell origin. Histopathologic evaluation reveals aggressive B-lineage neoplasm, with a large CD30+ B lineage neoplasm for which the combined features favor a B cell lymphoma, unclassifiable (BCL-U), with features intermediate between diffuse large B cell lymphoma and classic Hodgkin lymphoma. H&E shows architectural effacement by sheets of mitotically active large cells with oval nuclei, condensed chromatin, prominent nucleoli, and ample eosinophilic cytoplasm. Occasional multinucleate and bizarre forms are noted. Immunohistochemical stains show CD20 negativity consistent with clinical history of rituximab. B cell lineage confirmed by CD79a and Pax5. CD5 highlights scattered T cells. 10x magnification, expect inlet 40X. The analyses were conducted during the diagnostic assessment of the patients or as correlative exploratory analyses (qPCR) and as such were performed once. Abbreviations: H&E: hematoxylin and eosin.
Extended Data Fig. 2 Histopathological evaluation of the non-small cell lung cancer.
H&E staining; 2x and 10x magnification. Immunohistochemistry for p63 and CK5/6; 2x magnification. H&E sections show invasive poorly differentiated carcinoma with marked nuclear enlargement and atypia (10x image) infiltrating into the lung parenchyma and with large areas of necrosis. Immunohistochemical stains showed tumor cells staining strongly positive for CK5/6 and p63 and supported the diagnosis of invasive poorly differentiated squamous cell carcinoma. The analyses were conducted during the diagnostic assessment of the patients or as correlative exploratory analyses (qPCR) and as such were performed once. Abbreviations: H&E: hematoxylin and eosin staining. NSCLC: non-small cell lung cancer.
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Ghilardi, G., Fraietta, J.A., Gerson, J.N. et al. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med 30, 984–989 (2024). https://doi.org/10.1038/s41591-024-02826-w
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DOI: https://doi.org/10.1038/s41591-024-02826-w
