T-Zell-rekrutierende Immuntherapien des B-Zell-Lymphoms – bald in allen Therapielinien?

Mit Rituximab hat die Immuntherapie bereits vor Jahrzehnten Einzug in die Routinebehandlung von B-Zell-Lymphomen gehalten. Die Zulassung neuer bispezifischer T-Zell-rekrutierender Antikörper und der adoptiven Immuntherapie mit CAR-T-Zellen bringt tiefgreifende Änderungen der Therapiealgorithmen bei aggressiven und indolenten Lymphomen mit sich. Im Folgenden werden die wichtigsten aktuell zugelassenen T-Zell-rekrutierenden Behandlungsstrategien vorgestellt.

Abstract

The introduction of immunologically targeted therapies has represented a significant advancement in the treatment of B-cell lymphomas, particularly aggressive B-cell lymphoma. CD19 CAR-T cells such as Axicabtagen-Ciloleucel (Axi-cel) and Lisocabtagen Maraleucel (Liso-cel) have been approved since 2022 and 2023, respectively, for second-line therapy of Diffuse Large B-Cell Lymphomas (DLBCL), when there is primary refractory disease or relapse within 12 months after the end of first-line therapy. These therapies result in a significant improvement in progression-free survival compared to the previous standard therapy (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation). Especially in elderly patients or patients with underlying medical conditions, CAR-T cell therapies like Axi-cel and Liso-cel demonstrate acceptable tolerability and high efficacy.

Furthermore, bispecific T-cell-engaging antibodies (“bispecifics”) such as Glofitamab, Epcoritamab, and Mosunetuzumab also represent promising treatment options for patients with relapsed disease after failure of second- or later line therapy and show efficacy even in a subset of patients relapsing after CD19 CAR-T cells. However, randomized study results for these substances are not yet available. They are expected to be used in earlier lines of therapy in the future, especially in combination with standard chemotherapy regimens. Common side effects of bispecific antibody therapies are cytokine release syndrome (CRS) and immune-mediated cytopenias, whereas immune-cell associated neurotoxicity syndrome (ICANS) is relatively rare compared to CD19 CAR T cells. In summary, bispecifics represent a novel, highly effective immunotherapy for the treatment of lymphomas with a very favourable toxicity profile.

Kernaussagen

• CAR-T-Zellen und bispezifische Antikörperkonstrukte sind T-Zell-rekrutierende Behandlungskonzepte: Sie induzieren mittels patienteneigenen T-Zellen eine T-Zell-Antwort gegen B-Zell-Lymphomzellen.

• Die in der Behandlung von B-Zell-Lymphomen zur Anwendung kommenden CAR-T-Zell-Präparate sind alle gegen CD19 als B-Zell-Antigen gerichtet, unterscheiden sind aufgrund verschiedener kostimulatorischer Domänen aber im Nebenwirkungsprofil (und möglicherweise auch in ihrer Anti-Lymphom-Wirksamkeit). Zulassungen existieren für DLBCLs (nach Versagen der Erstlinientherapie), für Mantelzelllymphome und follikuläre Lymphome (nach Versagen der Zweitlinientherapie).

• Bispezifische Antikörper in der Behandlung von B-Zell-Lymphomen erkennen CD20 auf B-Zellen. Zulassungen existieren für DLBCLs und für follikuläre Lymphome (jeweils nach Versagen der Zweitlinientherapie).

• CAR-T-Zellen und Bispecifics sind mit einer Reihe spezifischer Nebenwirkungen assoziiert (CRS, ICANS und a.e. immunvermittelten Zytopenien), deren Management spezifische Expertise erfordert. Von besonderer Bedeutung auch im längerfristigen Verlauf nach Therapie sind Infektionen, die ein schnelles ärztliches Eingreifen erfordern.

Schlüsselwörter

Immuntherapie - B-Zell-Lymphom - CAR-T-Zellen - bispezifische Antikörper - ADC

Keywords

immunotherapy - B-cell lymphoma - CAR T cells - bispecific antibodies - ADC

Publication History

Article published online:
15 May 2024

• Literatur

• 1 Locke FL, Miklos DB, Jacobson CA. et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. New Engl J Med 2021; 386: 640-654
• 2 Kamdar M, Solomon SR, Arnason J. et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet 2022; 99: 2294-2308
• 3 Westin JR, Oluwole OO, Kersten MJ. et al. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med 2023; 389 (02) 148-157
• 4 Iacoboni G, Navarro V, Martín-López AÁ. et al. Recent Bendamustine Treatment Before Apheresis Has a Negative Impact on Outcomes in Patients With Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy. J Clin Oncol 2024; 42 (02) 205-217
• 5 Kersten MJ, Farooq U, Rapoport AP. et al. Improved Overall Survival with Axicabtagene Ciloleucel Vs Standard of Care in Second-Line Large B-Cell Lymphoma Among the Elderly: A Subgroup Analysis of ZUMA-7. Blood 2023; 42: 1761
• 6 Houot R, Bachy E, Cartron G. et al. S233: Axicabtagene ciloleucel as second-line therapy for large B cell lymphoma in transplant ineligible patients: final analysis of Alycante, a phase 2 lysa study. HemaSphere 2023; 7: e56791ba
• 7 Brisou G, Cartron G, Bachy E. et al. Real World Data of Axicabtagene Ciloleucel As Second Line Therapy for Patients with Large B Cell Lymphoma: First Results of a Lysa Study from the French Descar-T Registry. Blood 2023; 42: 5138
• 8 Sehgal A, Hoda D, Riedell PA. et al. Lisocabtagene Maraleucel as Second-Line Therapy for R/R Large B-Cell Lymphoma in Patients Not Intended for Hematopoietic Stem Cell Transplant: Final Analysis of the Phase 2 PILOT Study. Blood 2023; 42: 105
• 9 Lenz G, Chapuy B, Glaß B. et al. Diffuses großzelliges B-Zell-Lymphom — Onkopedia. Accessed March 18, 2024 at: https://www.onkopedia.com/de/onkopedia/guidelines/diffuses-grosszelliges-b-zell-lymphom/@@guideline/html/index.html
• 10 Wang M, Munoz J, Goy A. et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med 2020; 382: 1331-1342
• 11 Wang Y, Jain P, Locke FL. et al. Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. J Clin Oncol 2023; 41: 2594-2606
• 12 Hess G, Dreyling M, Oberic L. et al. Indirect treatment comparison of brexucabtagene autoleucel (ZUMA-2) versus standard of care (SCHOLAR-2) in relapsed/refractory mantle cell lymphoma. Leuk Lymphoma 2024; 65: 14-25
• 13 Neelapu SS, Chavez JC, Sehgal AR. et al. Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood 2024; 43: 496-506
• 14 Dreyling M, Fowler NH, Dickinson M. et al. Durable Response After Tisagenlecleucel in Adults With Relapsed/Refractory Follicular Lymphoma: ELARA Trial Update. Blood 2024;
• 15 Salles G, Schuster SJ, Dreyling M. et al. Efficacy comparison of tisagenlecleucel vs usual care in patients with relapsed or refractory follicular lymphoma. Blood Adv 2022; 6: 5835-5843
• 16 Ghione P, Palomba ML, Patel AR. et al. Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma. Blood 2022; 40: 851-860
• 17 Fowler NH, Dickinson M, Dreyling M. et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 2022; 8: 325-332
• 18 Jacobson CA, Chavez JC, Sehgal AR. et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2022; 3: 91-103
• 19 Dickinson MJ, Carlo-Stella C, Morschhauser F. et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 2022; 387: 2220-2231
• 20 Iacoboni G, Iraola-Truchuelo J, Mussetti A. et al. Salvage Treatment with Novel Agents Is Preferable to Standard Chemotherapy in Patients with Large B-Cell Lymphoma Progressing after Chimeric Antigen Receptor T-Cell Therapy. Blood 2022; 40: 378-380
• 21 Di Blasi R, Le Gouill S, Bachy E. et al. Outcomes of patients with aggressive B-Cell lymphoma after failure of anti-CD19 CAR T-Cell Therapy: A DESCAR-T analysis. Blood 2022; 40: 2584-2593
• 22 Thieblemont C, Phillips T, Ghesquieres H. et al. Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell–Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol 2023; 41: 2238-2247
• 23 Budde LE, Assouline S, Sehn LH. et al. Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study. J Clin Oncol 2022; 40: 481-491
• 24 Bosch F, Kuruvilla J, Vassilakopoulos TP. et al. Indirect Treatment Comparisons of Mosunetuzumab With Third- and Later-Line Treatments for Relapsed/Refractory Follicular Lymphoma. Clin Lymphoma Myeloma Leuk 2024; 24: 105-121
• 25 Rejeski K, Subklewe M, Aljurf M. et al. Immune Effector Cell-Associated Hematotoxicity (ICAHT): EHA/EBMT Consensus Grading and Best Practice Recommendations. Blood 2023; 142: 865-877
• 26 Neelapu SS, Locke FL, Bartlett NL. et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. New Engl J Medicine 2017; 377 (26) 2531-2544
• 27 Schuster SJ, Bishop MR, Tam CS. et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. New Engl J Medicine 2018; 380 (01)
• 28 Abramson JS, Solomon SR, Arnason J. et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood 2022; 141 (14) 1675-1684
• 29 Abramson JS, Palomba ML, Gordon LI. 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: 839-852