Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.

Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium.

Wang Y, Jain P, Locke FL, Maurer MJ, Frank MJ, Munoz JL, Dahiya S, Beitinjaneh AM, Jacobs MT, Mcguirk JP, Vose JM, Goy A, Andreadis C, Hill BT, Dorritie KA, Oluwole OO, Deol A, Paludo J, Shah B, Wang T, Banerjee R, Miklos DB, Rapoport AP, Lekakis L, Ghobadi A, Neelapu SS, Lin Y, Wang ML, Jain MD.J Clin Oncol. 2023 Feb 8:JCO2201797. doi: 10.1200/JCO.22.01797. Online ahead of print.PMID: 36753699

The study reported “real-world” data on the efficacy and safety of brexucabtagene autoleucel (brexu-cel) in patients with relapsed or refractory mantle cell lymphoma (MCL). Interestingly, of leukapheresed patients, 79% would not have met ZUMA-2 (the pivotal trial leading to brexu-cel FDA approval) eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively, comparable to ZUMA-2. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. Additional notable findings are a relatively high rate of 1-year non-relapse mortality, primarily due to infections, and that recent bendamustine exposure may contribute to inferior outcomes.

A validated composite comorbidity index predicts outcomes of CAR T-cell therapy in patients with diffuse large B cell lymphoma.

Shouse G, Kaempf A, Gordon MJ, Artz AS, Yashar D, Sigmund AM, Smilnak G, Bair SM, Mian A, Fitzgerald LA, Bajwa A, Jaglowski SM, Bailey N, Shadman M, Patel K, Stephens DM, Kamdar M, Hill BT, Gauthier J, Karmali R, Nastoupil LJ, Kittai AS, Danilov AV.Blood Adv. 2023 Feb 3:bloodadvances.2022009309. doi: 10.1182/bloodadvances.2022009309. Online ahead of print.PMID: 36735393

Authors developed a comorbidity score (Severe4) in a multicenter cohort including 577 lymphoma patients treated with CD19-directed CAR-T. Comorbidities comprising the score were selected using a random forest approach. The score was associated with overall survival and progression-free survival both in the development cohort as well as an independent validation cohort.

CD19-CAR-T cells are an effective therapy of post-transplant relapse in B- ALL patients: Real-World Data from Germany.

Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bücklein VL, Bonig H, Cario G, Einsele H, Holtick U, Koenecke C, Bakhtiar S, Künkele A, Meisel R, Mueller F, Müller I, Penack O, Rettinger E, Sauer MG, Schlegel PG, Soerensen J, von Stackelberg A, Strahm B, Feuchtinger T, Hauer J, Jarisch A.Blood Adv. 2023 Jan 6:bloodadvances.2022008981. doi: 10.1182/bloodadvances.2022008981. Online ahead of print.PMID: 36607834

A retrospective multicenter study from Germany reporting outcomes on pediatric and young adult patients (n=81) with B-acute lymphoblastic leukemia (ALL), who had received Tisagenlecleucel (Tisa-cel) for relapsed/refractory B-acute lymphoblastic leukemia (ALL) as standard of care. Sixty five patients (80%) were previously treated with an allogeneic hematopoietic cell transplantation (allo-HCT).

Severe CRS and ICANS were infrequent. Day 28 CR rate was high (71/81; 88%); of note 54% of patients were in morphological CR at time of lymphodepleting chemotherapy. Notably, all patients in CR and with available MRD testing were MRD negative. The vast majority of CR patients (70/71) did not receive any consolidation treatment after CAR-T. NRM rates were low. Event-free survival (EFS) and overall survival probability at 2 years were 45.3% and 53.2%, respectively. EFS was not different in patients without (n=16, 55.0%) vs. with prior alloHSCT (n=65, 43.4%). However, early relapse (<6 months) following the pre-CAR-T allo-HCT was a poor prognostic factor. Overall, this study provides real-world experience and suggests the potential benefit of Tisa-cel for B-ALL patients post-allo-HCT.

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.

Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S.N Engl J Med. 2023 Feb 10. doi: 10.1056/NEJMoa2213614. Online ahead of print.PMID: 36762851

This international, open-label, phase 3 trial (KarMMa-3), randomized patients with relapsed and refractory multiple myeloma who had received two to four regimens previously to idecabtagene vicleucel (ide-cel) and standard anti-myeloma regimens (2:1 randomization). The results showed that ide-cel had a higher overall response rate and longer duration of response compared to standard regimens. However, ide-cel was also associated with more adverse events, including cytokine release syndrome and neurotoxicity. The study suggests that ide-cel could be an effective treatment option for patients with relapsed and refractory multiple myeloma, but its safety profile should be carefully monitored.

GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial.

Zhang M, Wei G, Zhou L, Zhou J, Chen S, Zhang W, Wang D, Luo X, Cui J, Huang S, Fu S, Zhou X, Tang Y, Ding X, Kuang J, He XP, Hu Y, Huang H.Lancet Haematol. 2023 Feb;10(2):e107-e116. doi: 10.1016/S2352-3026(22)00372-6.PMID: 36725117 Clinical Trial.

POLARIS  is a phase 1 clinical trial that evaluated the safety and efficacy of GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. The trial recruited 13 patients, of which 10 patients received the CAR T product. Nine patients were assigned to the dose escalation phase. The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 106 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. There were no serious adverse events and no treatment-related deaths, but grade 3 neutropenia and thrombocytopenia occurred in 90-100% of patients. Ten (100%) had an overall response, of whom 6 (60%) had a stringent complete response, and 4 (40%) had very good partial response. These results and other previously published studies suggest that GPRC5D is an active target for immunotherapy in multiple myeloma.

T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells.

Battram AM, Oliver-Caldés A, Suárez-Lledó M, Lozano M, Bosch I Crespo M, Martínez-Cibrián N, Cid J, Moreno DF, Rodríguez-Lobato LG, Urbano-Ispizua A, Fernández de Larrea C.Mol Ther Methods Clin Dev. 2022 Jun 22;26:207-223. doi: 10.1016/j.omtm.2022.06.010. eCollection 2022 Sep 8.PMID: 35859694

An interesting analysis indicating the use of G-CSF to mobilize hematopoietic progenitor cells before autologous hematopoietic cell transplantation has a minimal impact on T-cell phenotype and is not deleterious for anti-BCMA CAR-T cells. The authors conclude that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture.

CD19-targeted CAR T cells in refractory antisynthetase syndrome

Fabian Müller, Sebastian Boeltz, Johannes Knitza, Michael Aigner, Simon Völkl Soraya Kharboutli, Hannah Reimann, Jule Taubmann, Sascha Kretschmann, Wolf Rösler, Bernhard Manger, Jochen Wacker, Dimitrios Mougiakakos, Samir Jabari, Rolf Schröder, Michael Uder, Frank Roemer, Gerhard Krönke, Andreas Mackensen, Georg Schet.

The Lancet, Published:February 15, 2023DOI:https://doi.org/10.1016/S0140-6736(23)00023-5.

A case report of a patient with refractory antisynthetase syndrome and related refractory idiopathic inflammatory myopathy treated with CD19-directed autologous CAR-T cells (Miltenyi Biotech; Bergisch Gladbach, Germany). Remarkably CAR-T cell infusion led to the complete resolution of the antisynthetase syndrome despite the cessation of all immunosuppressive drugs. This resolution was sustained even after the reconstitution of B cells. Long-term follow-up will be needed to assess whether CAR T-cell treatment might have permanently resolved antisynthetase syndrome in this patient.

Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium.
Hansen DK, Sidana S, Peres LC, Colin Leitzinger C, Shune L, Shrewsbury A, Gonzalez R, Sborov DW, Wagner C, Dima D, Hashmi H, Kocoglu MH, Atrash S, Simmons G, Kalariya N, Ferreri C, Afrough A, Kansagra A, Voorhees P, Baz R, Khouri J, Alsina M, McGuirk J, Locke FL, Patel KK.J Clin Oncol. 2023 Jan 9:JCO2201365. doi: 10.1200/JCO.22.01365. Online ahead of print.PMID: 36623248

The first report of real world experience with Idecabtagene Vicleucel for refractory multiple myeloma. See also Dr. Doris Hansen related report in IACH News.

Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.
Mailankody S, Matous JV, Chhabra S, Liedtke M, Sidana S, Oluwole OO, Malik S, Nath R, Anwer F, Cruz JC, Htut M, Karski EE, Lovelace W, Dillon M, Butz E, Ying W, Balakumaran A, Kumar SK.Nat Med. 2023 Jan 23. doi: 10.1038/s41591-022-02182-7. Online ahead of print.PMID: 36690811

A first-in-human phase 1 trial in patients with heavily pretreated multiple myeloma, that demonstrates feasibility, acceptable safety and preliminary evidence of anti-myeloma efficacy for ALLO-715, the first allogeneic BCMA-targeted CAR T therapy.

Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.
Newman H, Li Y, Liu H, Myers RM, Tam V, DiNofia A, Wray L, Rheingold SR, Callahan C, White C, Baniewicz D, Winestone LE, Kadauke S, Diorio C, June CH, Getz K, Aplenc R, Teachey DT, Maude SL, Grupp SA, Bona K, Barz Leahy

A retrospective study exploring the influence of socioeconomic status on outcomes of CD19-directed CAR T-cell therapy in children with acute lymphoblastic leukemia (ALL). CAR T produced equivalent remission and survival for children with relapsed/refractory ALL, regardless of household-poverty or neighborhood-opportunity.

Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy.
Hubbeling H, Silverman EA, Michaud L, Tomas AA, Shouval R, Flynn J, Devlin S, Wijetunga NA, Tringale KR, Batlevi C, Dahi P, Giralt S, Lin R, Park J, Scordo M, Sauter C, Shah G, Hajj C, Salles G, Schoder H, Palomba ML, Perales MA, Yahalom J, Imber BS.Transplant Cell Ther. 2022 Dec 30:S2666-6367(22)01870-X. doi: 10.1016/j.jtct.2022.12.021. Online ahead of print.PMID: 36587744

A retrospective study demonstrating that bridging with radiation therapy before CAR-T cells in large B-cell lymphoma may “convert” poor-risk patients to better risk.

 Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study.
Abramson JS, Solomon SR, Arnason JE, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers PGNJ, Hernandez-Ilizaliturri FJ, Izutsu K, Morschhauser F, Lunning MA, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M.Blood. 2022 Dec 21:blood.2022018730. doi: 10.1182/blood.2022018730. Online ahead of print.PMID: 36542826

This global, phase 3 study compared lisocabtagene maraleucel (liso-cel) with standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL).   The study demonstrates significant improvements in EFS, CR rate, and PFS for liso-cel over SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL.

Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
Sworder BJ, Kurtz DM, Alig SK, Frank MJ, Shukla N, Garofalo A, Macaulay CW, Shahrokh Esfahani M, Olsen MN, Hamilton J, Hosoya H, Hamilton M, Spiegel JY, Baird JH, Sugio T, Carleton M, Craig AFM, Younes SF, Sahaf B, Sheybani ND, Schroers-Martin JG, Liu CL, Oak JS, Jin MC, Beygi S, Hüttmann A, Hanoun C, Dührsen U, Westin JR, Khodadoust MS, Natkunam Y, Majzner RG, Mackall CL, Diehn M, Miklos DB, Alizadeh AA.Cancer Cell. 2023 Jan 9;41(1):210-225.e5. doi: 10.1016/j.ccell.2022.12.005. Epub 2022 Dec 29.PMID: 36584673

Longitudinal concurrent profiling of tumor-derived circulating tumor DNA as well as CAR19-derived cell-free DNA in large B-cell lymphoma patients undergoing treatment with axicabtagene ciloleucel. This combined strategy allowed for the simultaneous characterization of molecular response, identification of genomic alterations associated with treatment failure, and profiling of CAR19 activity, thus facilitating integrative analyses of how these factors work in concert to lead to CAR19 resistance.