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Radiation and Chimeric Antigen Receptor T-cell Therapy in B-cell Non-Hodgkin Lymphomas

  • Lymphoma (JL Muñoz, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Chimeric antigen receptor T-cell therapy (CAR-T) is a revolutionary advancement in the management of chemotherapy refractory B-cell non-Hodgkin lymphomas representing a potentially curative therapy in scenarios that were previously only palliative. CAR-T cell therapy is associated with unique toxicities as well as practical challenges. One of those challenges is how to manage active lymphoma during the weeks-long CAR-T manufacturing process. Radiation therapy, steroids, and systemic therapy have all been used for what would be considered “bridging therapy” during this time frame. Radiation therapy is a particularly attractive strategy given its proven efficacy in chemotherapy refractory lymphomas; ability to stabilize patients, debulk disease, and palliate symptoms; as well as its potential to enhance the expansion and activity of CAR-T cells. Optimal dose, timing, and method of delivery are yet to be established though there is consensus that it should occur after apheresis if being used as a pre-treatment bridge. Another practical challenge is the management of patients in whom CAR-T cells fail. There is a potential emerging role for salvage radiation therapy, in select patients, for either palliation or as a means to get patients another potentially curative therapy. Collaborative well-designed prospective clinical trials are needed to definitively establish the role for radiation therapy (before or after CAR-T therapy) as well as define the impact on CAR-T cell activity/persistence and associated toxicity.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019;94(S1):S3–s9.

    Article  CAS  PubMed  Google Scholar 

  2. Chavez JC, Locke FL. CAR T cell therapy for B-cell lymphomas. Best Pract Res Clin Haematol. 2018;31(2):135–46.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839–52.

    Article  PubMed  Google Scholar 

  4. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56.

    Article  CAS  PubMed  Google Scholar 

  6. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, de Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma. 1995;18(5-6):385–97.

    Article  CAS  PubMed  Google Scholar 

  8. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 2005;26(2):111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119(24):5688–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010;116(12):2040–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nair R, Neelapu SS. The promise of CAR T-cell therapy in aggressive B-cell lymphoma. Best Pract Res Clin Haematol. 2018;31(3):293–8.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, 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. 2019;20(1):31–42.

    Article  CAS  PubMed  Google Scholar 

  14. Chow VA, Gopal AK, Maloney DG, Turtle CJ, Smith SD, Ujjani CS, Shadman M, Cassaday RD, Till BG, Tseng YD, Warren EH, Shustov AR, Menon MP, Bhark S, Acharya UH, Mullane E, Hannan LM, Voutsinas JM, Gooley TA, Lynch RC. Outcomes of patients with large B-cell lymphomas and progressive disease following CD19-specific CAR T-cell therapy. Am J Hematol. 2019;94(8):E209–e13.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jacobson C, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, et al. Primary analysis of Zuma-5: a phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients with relapsed/refractory (R/R) indolent non-hodgkin lymphoma (iNHL). Blood. 2020;136(Supplement 1):40–1.

    Google Scholar 

  16. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, Komanduri KV, Lin Y, Jain N, Daver N, Westin J, Gulbis AM, Loghin ME, de Groot JF, Adkins S, Davis SE, Rezvani K, Hwu P, Shpall EJ. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.

    Article  CAS  PubMed  Google Scholar 

  18. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, López JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ng AK, Yahalom J, Goda JS, Constine LS, Pinnix CC, Kelsey CR, Hoppe B, Oguchi M, Suh CO, Wirth A, Qi S, Davies A, Moskowitz CH, Laskar S, Li Y, Mauch PM, Specht L, Illidge T. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018;100(3):652–69.

    Article  PubMed  Google Scholar 

  20. Hoppe BS, Moskowitz CH, Filippa DA, Moskowitz CS, Kewalramani T, Zelenetz AD, Yahalom J. Involved-field radiotherapy before high-dose therapy and autologous stem-cell rescue in diffuse large-cell lymphoma: long-term disease control and toxicity. J Clin Oncol. 2008;26(11):1858–64.

    Article  PubMed  Google Scholar 

  21. Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, Bittenbring J, Hänel M, Wilhelm S, Schubert J, Schmitz N, Löffler M, Rübe C, Pfreundschuh M. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014;32(11):1112–8.

    Article  PubMed  Google Scholar 

  22. Tseng YD, Chen YH, Catalano PJ, Ng A. Rates and durability of response to salvage radiation therapy among patients with refractory or relapsed aggressive non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2015;91(1):223–31.

    Article  PubMed  Google Scholar 

  23. Hoppe BS, Moskowitz CH, Zhang Z, Maragulia JC, Rice RD, Reiner AS, et al. The role of FDG-PET imaging and involved field radiotherapy in relapsed or refractory diffuse large B-cell lymphoma. Bone Marrow Transplant. 2009;43(12):941–8.

    Article  CAS  PubMed  Google Scholar 

  24. Martens C, Hodgson DC, Wells WA, Sun A, Bezjak A, Pintilie M, Crump M, Gospodarowicz MK, Tsang R. Outcome of hyperfractionated radiotherapy in chemotherapy-resistant non-Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys. 2006;64(4):1183–7.

    Article  PubMed  Google Scholar 

  25. Locke FL, Rossi JM, Neelapu SS, Jacobson CA, Miklos DB, Ghobadi A, Oluwole OO, Reagan PM, Lekakis LJ, Lin Y, Sherman M, Better M, Go WY, Wiezorek JS, Xue A, Bot A. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nastoupil LJ, Jain MD, Feng L, Spiegel JY, Ghobadi A, Lin Y, Dahiya S, Lunning M, Lekakis L, Reagan P, Oluwole O, McGuirk J, Deol A, Sehgal AR, Goy A, Hill BT, Vu K, Andreadis C, Munoz 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. 2020;38(27):3119–28.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, Lazaryan A, Krivenko G, Davila ML, Liu HD, Falchook AD, Dahiya S, Rapoport AP, Kim S, Locke FL, Robinson TJ. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol Biol Phys. 2019;105(5):1012–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. • Wright CM, LaRiviere MJ, Baron JA, Uche C, Xiao Y, Arscott WT, et al. Bridging radiation therapy before commercial chimeric antigen receptor T-cell therapy for relapsed or refractory aggressive B-cell lymphoma. Int J Radiat Oncol Biol Phys. 2020;108(1):178–88. This retrospective series compared outcomes/toxicity in patients who did and did not receive RT as a bridge to CAR-T cell therapy and raises the question of whether bridging RT can help mitigate CAR-T associated toxicities

    Article  PubMed  Google Scholar 

  29. Qu C, Ping N, Kang L, Liu H, Qin S, Wu Q, Chen X, Zhou M, Xia F, Ye A, Kong D, Li C, Yu L, Wu D, Jin Z. Radiation priming chimeric antigen receptor T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma with high tumor burden. J Immunother. 2020;43(1):32–7.

    Article  CAS  PubMed  Google Scholar 

  30. Pinnix CC, Gunther JR, Dabaja BS, Strati P, Fang P, Hawkins MC, Adkins S, Westin J, Ahmed S, Fayad L, Lee HJ, Nair R, Steiner RE, Iyer SP, Rodriguez MA, Wang M, Flowers C, Neelapu SS, Nastoupil LJ. Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma. Blood Adv. 2020;4(13):2871–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Imber B, Palomba ML, DeSelm C, Batlevi CL, Dahi PB, Giralt SA, et al. MSKCC early experience using radiotherapy as a bridging strategy for relapsed diffuse large B cell lymphoma before CD19 CAR T therapy. Blood. 2019;134(Supplement_1):3238.

    Article  Google Scholar 

  32. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83(4):1306–10.

    Article  CAS  PubMed  Google Scholar 

  33. Routman DM, Garant A, Lester SC, Day CN, Harmsen WS, Sanheuza CT, Yoon HH, Neben-Wittich MA, Martenson JA, Haddock MG, Hallemeier CL, Merrell KW. A comparison of grade 4 lymphopenia with proton versus photon radiation therapy for esophageal cancer. Adv Radiat Oncol. 2019;4(1):63–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fang P, Shiraishi Y, Verma V, Jiang W, Song J, Hobbs BP, Lin SH. Lymphocyte-sparing effect of proton therapy in patients with esophageal cancer treated with definitive chemoradiation. Int J Part Ther. 2018;4(3):23–32.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Saifi O, Kharfan-Dabaja MA, Zeidan YH, Peterson J, Rule WG, Lester SC, Hoppe BS. Proton therapy as a bridging treatment in CAR T-cell therapy for relapsed and refractory large B-cell lymphoma: is there a role? Int J Part Ther. 2020;7(1):13–20.

    Article  PubMed  PubMed Central  Google Scholar 

  36. • DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, Sadelain M. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther. 2018;26(11):2542–52. This paper serves as proof of concept that low dose radiation therapy may minimize risk of antigen escape which is a known problematic cause of CAR-T cell therapy failure

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Flynn JP, O'Hara MH, Gandhi SJ. Preclinical rationale for combining radiation therapy and immunotherapy beyond checkpoint inhibitors (i.e., CART). Transl Lung Cancer Res. 2017;6(2):159–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jin L, Ge H, Long Y, Yang C, Chang YE, Mu L, et al. CD70, a novel target of CAR T-cell therapy for gliomas. Neuro Oncol. 2018;20(1):55–65.

    Article  CAS  PubMed  Google Scholar 

  39. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008;180(5):3132–9.

    Article  CAS  PubMed  Google Scholar 

  40. Minn I, Rowe SP, Pomper MG. Enhancing CAR T-cell therapy through cellular imaging and radiotherapy. Lancet Oncol. 2019;20(8):e443–e51.

    Article  CAS  PubMed  Google Scholar 

  41. Weiss T, Weller M, Guckenberger M, Sentman CL, Roth P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res. 2018;78(4):1031–43.

    Article  CAS  PubMed  Google Scholar 

  42. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–7.

    Article  CAS  PubMed  Google Scholar 

  43. Cheng JN, Luo W, Sun C, Jin Z, Zeng X, Alexander PB, et al. Radiation-induced eosinophils improve cytotoxic T lymphocyte recruitment and response to immunotherapy. Sci Adv. 2021;7(5):eabc7609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Smith EL, Mailankody S, Staehr M, Wang X, Senechal B, Purdon TJ, Daniyan AF, Geyer MB, Goldberg AD, Mead E, Santomasso BD, Landa J, Rimner A, Riviere I, Landgren O, Brentjens RJ. BCMA-targeted CAR T-cell therapy plus radiotherapy for the treatment of refractory myeloma reveals potential synergy. Cancer Immunol Res. 2019;7(7):1047–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Buchwald ZS, Wynne J, Nasti TH, Zhu S, Mourad WF, Yan W, Gupta S, Khleif SN, Khan MK. Radiation, immune checkpoint blockade and the abscopal effect: a critical review on timing, dose and fractionation. Front Oncol. 2018;8:612.

    Article  PubMed  PubMed Central  Google Scholar 

  46. • Imber BS, Sadelain M, DeSelm C, Batlevi C, Brentjens RJ, Dahi PB, Giralt S, Park JH, Sauter C, Scordo M, Shah G, Perales MA, Palomba ML, Yahalom J. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol. 2020;190(1):45–51. At time of publication, this is the only study specifically reporting utility of radiation therapy in patients with progressive lymphoma post CAR-T cell therapy

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Mayo Clinic Alix School of Medicine, Scottsdale, AZ, USA

    Anagha Deshpande

  2. Mayo Clinic Department of Radiation Oncology, Phoenix, AZ, USA

    William Rule MD

  3. Mayo Clinic Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA

    Allison Rosenthal DO

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Deshpande, A., Rule, W. & Rosenthal, A. Radiation and Chimeric Antigen Receptor T-cell Therapy in B-cell Non-Hodgkin Lymphomas. Curr. Treat. Options in Oncol. 23, 89–98 (2022). https://doi.org/10.1007/s11864-021-00935-z

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