- From innovation to implementation - CAR T for r/r LBCL
- The future of cellular therapy in MM
From innovation to implementation - CAR T for r/r LBCL
The aim of the satellite symposium is to discuss the latest advances of the role of CAR T cell therapy in r/r LBCL and the strategies to optimize the implementation of the therapy, to gain insights into the recent developments of cell therapy in r/r MM, the application, opportunities, and future directions and last but not least to address the impact of CART cell therapy in the evolving treatment landscape of r/r LBCL and r/r MM
From innovation to implementation: CAR T for R/R LBCL
Presenter: Stephan Mielke, Scientific Director of the Cancer Center, Head of Allogeneic Stem Cell Transplantation and Cell Therapy (CAST), Professor of Hematology and Cellular Therapy, Karolinska Comprehensive Cancer Center Karolinska Institutet and University Hospital, Stockholm , Sweden
Brief summary of Mielke's presentation:
Approved anti-CD19 CART cell products for R/R aggressive B-cell NHL:
- Axicabtagene Ciloleucel (axi-cel) (Neelapu SS, et al. N Engl J Med. 2017;377:2531-44) vgl. Yescarta ® Compendium® and Oncoletter
- Tisagenlecleucel (tisa-cel) (Schuster SJ, et al. N Engl J Med. 2019;380:45-56) vgl. Kymriah® Compendium® and Oncoletter
- Lisocabtagene maraleucel (liso-cel) (Abramson JS, et al. Lancet. 2020;396:839-52)vgl. Breyanzi® (USA) Oncoletter
Trials assessing CART cell therapies in R/R LBCL:
Please be aware: Trial information is listed for descriptive purposes. The presenter states that Inter-trial comparisons should not be made due to differences in study design, patient populations, treatment interventions, and duration of follow-up, among others. There cannot be made direct comparisons or drawn conclusions from one trial to another.
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≥ Third line Axi-cel (axicabtagene ciloleucel) in phase 1/2 in DLBCL, PMBCL, tFL and HGBCL R/R after ≥ prior therapies, including anti-CD20 mAb or anthracycline-based therapy or failed ASCT (ZUMA-1) NCT02348216 1. Locke Fl. el al. Lancet Oncol. 2019;20:31-42. 2. Jacobson C, et al. Presented at ASH 2020; abstract 1187. 3. Jacobson C, et al. Presented at ASH 2021; abstract 1764. Tisa-cel (tisagenlecleucel) in phase 2 in LBCL R/R to ≥ prior lines of therapy, chemotherapy including rituximab or anthracycline, failed ASCT, or being ineligible for ASCT) (JULIET) NCT02445248 Results: ORR: 53% (n = 115} CR: 39%, Median PFS: 2.9 mo (F/U: 40.3 mo), Median OS: 11.1 mo) 1. TEAEs of interest Grade ≥ 3 CRS or NE, (%) 1: CRS 23, NE 11, Prolonged cytopenias 34. 1,2 1. Schuster SI et al. Lancet Oncol. 2021; 22:1403-15. 2. Schuster S, et al. N Engl J Med. 2019;380:45-56. Liso-cel (lisocabtagene maraleucel) in phase 1 in DLBCL, NOS, HGBCL, PMBCL, and FL3B R/R to 2:2 prior lines of therapy, including rituximab, anthracycline-based therapy, and failed ASCT (TRANSCEND-NHL-001) NCT02631044 Results: ORR: 73% (n = 256} CR: 53%; 1 Median PFS: 6.8 mo (F/U: 24 mo), Median OS: 27.3 mo); 2 TEAEs of interest Grade ≥ 3 CRS or NE, (%) 2: CRS 2, NE 10, Prolonged cytopenias 37. 2 1. Abramson JS, et al. Lancet. 2020:396:839-52. 2. Abramson JS, et al. Presented at ASH 2021; abstract 2840. |
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Second line (No CART cell therapy has obtained regulatory approval for in 2L ≤ 12 months LBCL): Patients with LBCL primary refractory to or relapsed ≤12 months after ll therapy have poor outcomes with the current SOC, salvage CT followed by HDCT and ASCT three-year EFS rates are~ 20%. 4 Axi-cel vs SOC in phase 3 in DLBCL, HGBL, DLBCL arising from FL and T/HRLB-CL R/R, including rituximab or anthracycline-based therapy ≤ 12 months of first-line therapy, transplant eligible, (ZUMA-7) NCT03391466 1 Results: Median EFS: 8.3 mo (F/U: 24.9 mo), median OS: NR. Odds ratio, 5.31 (95% Cl 3.1-8.9); p < 0.0001; mPFS 14.7 vs 5.4; PFS @24 mo 46 vs 27%; OS @ 2y 61 vs 52%. TAEs of interest ≥ 3 (%) CRS 6, NE 21 vs 1, Prolonged cytopenias 29 vs 19. Grade ≥3 TEAEs occurred in 155 (91%) axi-cel and 140 (83%} SOC patients Tisa-cel vs SOC in phase 3 in DLBCL, FL grade 3B, PMBCL, T/HRLB-CL, HGBCL R/R, anti-CD20 mAb and anthracycline-based therapy ≤ 12 months of first-line therapy, transplant eligible (BELINDA) NCT03570892 2 Results: Median EFS: 3 vs 3 mo (F/U: 10 mo); Median OS: 16.9 vs 15.3 mo; ORR @/after 12 weeks: 46.3 vs 42.5%; TAEs of interest ≥ 3 (%) CRS 4.9, NE 1.9, Prolonged cytopenias NR. Liso-cel vs SOC in phase 3 in DLBCL NOS, HGBCL, PMBCL, T/HRBCL, and FL3B R/R (anti-CD20 mAb and anthracycline- based therapy ≤ 12 months, transplant eligible (TRANSFORM) NCT03575351 3 Results: Median EFS: 10.1 vs 2.3 mo (F/U: 6.2 mo); PFS, median 14.8 vs 5.7 mo; ORR (%) 86 vs 48; EFS rate at 6 mo (%) 63 vs 33.4; 1. Locke FL. et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2116133 2. Bishop MR, et al. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2116596 3. Kamdar M, et al. Presented at ASH 2021; abstract 91. Oncoletter 4. GisselbrechtC, et al. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Liso-cel in phase 2 bei DLBCL (NOS), HGBCL, and FL G3B R/R ineligible for HOC and ASCT (TRANSCEND-PILOT) NCT03483103 |
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First line Results: CR: 78% ORR: 89% (F/U: 15.9 months); Median 24.5 mo; 12-mo OS rate 90.6%. %; TAEs of interest Grade ≥ 3 (%) CRS 8, NE 23. 1 1. Neelapu SS, et al. Oral presentation at ASH 2021; abstract 739 |
Failures usually occur early after infusion. The purpose of the study of Vercelllno L. et al. was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. In summary, risk factors identified for early progression at TD and at TT (median follow-up of 8.2 mo) were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).
Vercelllno L. et al. Blood Adv 2020 Nov 24;4(22):5607-5615. doi: 10.1182/bloodadvances.2020003001.
In Mielkes conclusion of his presentation the follow-up data from three pivotal trials clearly support ≥3rd line treatment in r/r LBCL. According to Mielke at a very early stage of implementation and optimal patient selection, manufacturing, timely accessibility, and team competence are critical for the outcome. "Real-world data from large registries are needed to improve soc treatment in the long run and see which product is optimal for certain subgroups of patients."
Data from three randomized trials in 2nd line treatment of r/r LBCL compared to SOC distinguish significantly in their design and should not be directly compared to each other. More follow-up on OS is needed before drawing final conclusions. Overall the results are promising.
more info:
EBMT Registry, December 2021.
All NCT links Accessed February 2022.
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This year's meeting covered a wide range of topics. In turn, VJHemOnc did interviews on the following topics such as deep science, translational, clinical and commercial development in the field of CAR-T. See these posts on the VJHemOnc events page
The future of cellular therapy in MM
Presenter: Salomon Manier (France), Médecin Hématologie CHU, Lille France
New generation immunotherapies in multiple myeloma:
- CART cell (1) e.g. ide-cel, cilta-cel, ALLO715, p-BCMA-101, CT053
- IgG-like bispecific antibody (2) e.g. AMG701, TNB-383B, Teclistamab, Talquetamab CC-93269, Elranatamab, Cevostamab, REGN5458
- Antibody-drug conjugate (7) e.g. Belantamab, MEDl2228
treatment targets for multiple myeloma:
BCMA (3)
- Selectively overexpressed in plasma cells
- Promotes proliferation and survival of MM cells
GPRC5D (4,5)
- Highly and selectively expressed in MM
- Distribution is similar to but independent of BCMA
FCRH5 (6)
- High levels of expression on MM cells
- Normally expressed in plasma cells only
CAR T cells in myeloma
All target BCMA except MCARH109 targets GPRC5D; all co-stimulated with 4-1BB, all autologous except ALLO-71 (Allogenic CD52 & TCR KO ) & P-BCMA-101 (autologous + piggyBac);
Please be aware: Trial information is listed for descriptive purposes. The presenter states that Inter-trial comparisons should not be made due to differences in study design, patient populations, treatment interventions, and duration of follow-up, among others. There cannot be made direct comparisons or drawn conclusions from one trial to another.
2nd generation CARs
Ide-cel - KarMMa (NCT03361748), Phase II (1) scFv: chimeric mouse; # of lines 6
Results:
Best overall response
• Primary (ORR >50%) and key secondary (CRR > 10%) endpoints met in the ide-cel-treated population
• ORR of 73% (95% Cl, 66-81; P<0.001*)
• CRR (CR/sCR) of 33% (95% Cl, 24.7-40.9; P<0.0001)
Median time to first response of 1.0 mo (range, 0.5-8.8); median time to CR of 2.8 mo (range, 1.0-11.8
Median follow-up of 13.3 mo across target dose levels (1b, updated results: 1c)
Progression-free survival and safety:
PFS increased with higher target dose; median PFS was 12 mo at 450 x 106 CART cells (1. )≥3 CRS event, 5.4%, Median onset, days (range) 1 (1-12), median duration 5 days (1-63); Hematological AEs, grade 3/4: Neutropenia 89%, Lymphopenia 27%, Thrombocytopenia 52%; ≥3 NT event 4%, Median onset, days (range) 2 (1-10), median duration 3 days (1-26);
Response rate by subgroup:
ORR was ≥65%, CR rate was ≥20% across all highrisk subgroups except R-ISS stage III. The presence of extramedullary disease and baseline tumor burden did not substantially affect ORR. Among high-risk subgroups treated with the highest target dose of 450 x 106 CAR T cells, ORR and CR rate were ≥75% and ≥ 19%, respectively, across all subgroups except R-ISS stage Ill; and by age group: ORR and CR rates in the elderly groups were comparable with those observed in the overall ide-cel treated population. Median time to first response was 1.0 month in both elderly groups and in the overall treated population. Older age did not have a significant impact on PFS. Survival data are immature with 66% of all ide-cel treated patients censored. 1d
Baseline patient and product correlates of CR/sCR: Patient characteristics including higher tumor burden. (sBCMA) and higher inflammation (D-dimer, ferritin) are identified as negative correlates of CR/sCR1. In practice, selecting patients with a lower tumor burdon and conzrolling tumor burden through use of optimal bridging therapies may help attaining CR/sCR after ide-cel treatment. 1e
T cell depletion after alkylating exposure (1f):
• T cell depletion was detectable up to 9 months after alkylating agent exposure
• Patients recently exposed to alkylating agents had higher overall rates of prior myeloma treatment regimens and fewer T cells in the PBMC material at harvest for CART cell manufacture
• Prior exposure to alkylating agents can reduce the quantity of T cells and could be a disadvantage for patients considering autologous CAR T cell therapy
Cilta-cel - CARTITUDE-1, Phase Ib/II (2) scFv: chimeric llama; # of lines 6
Results:
Efficacy response and safety:
At 2 years, 60.5% of patients are still progression-free (2,2c); progression-free survival (2): 2 year PFS, all patients: 60.5% (95% Cl, 48.5-70.4) and sCR patients: 2-year PFS: 71.0°I, (95% Cl, 57.6-80.9) Median PFS not reached (95°/4 Cl, 25.2-NE. safety (2c): ≥3 CRS event, 5%, Median onset, days (range) 7 (5-8), median duration 4 days (3-6); Hematological AEs, grade 3/4: Neutropenia 98%, Lymphopenia 99%, Thrombocytopenia62%; ≥3 NT event 10%, Median onset, days (range) 27 (16-73), median duration 4 days (3-7);
Academic
ARI0002h, Phase I/II (3) scFv: humanized; # of lines 4
Alternative manufacturing
P-BCMA-101 - PRIME, Phase I/II (4) scFv: chimeric mouse; # of lines 7
Human scFv
CT053, Phase I (5) scFv: human; # of lines 6
CT103A, Phase I/II (6) scFv: human; # of lines 4
Allo-CAR
ALLO-71 - UNIVERSAL, Phase I (7) scFv: human; # of lines 5 (investigational, not yet approved)
Results:
Safety (Grade 3) and efficacy: CRS 1 (2%), Neurotoxicity 0, GvHD 0, infection 7 (16%).
DL3 cohort (320M CAR T+ cells): FCA ALL (FCA39,-60,-90) ORR, 17 (71%), VGPR Rate, 11 (46%), CR/sCR Rate, 6 (25%), mDOR, 8.3 months (95% Cl 3.4-11.3), median F/U 3.8 months (range 0.5-11.2)
GPRCSD
MCARH109, Phase I (8) scFv: human; # of lines 8
Results:
Response and safety (Prior BCMA therapy) n=10: Partial response or better, 8(80%) Complete response or better 3(30%) BM MRD negativity, 5 (50%)
Response and safety (Prior CAR T therapy) n=8: Partial response or better, 6(75%) Complete response or better 3(38%) BM MRD negativity, 2 (25%)
Future plans for CART cell therapy
KarMMa3: Phase 3 study of ide-cel versus standard regimens in triple-class- exposed patients with 2-4 prior lines of therapy 9
CARTITUDE-4: Phase 3 study of cilta-cel versus standard triplet regimens in relapsed and lenalidomide-refractory MM 10
The presenter concludes that
• CAR-T cell therapy in MM approved
• Main target is BCMA, but also GPRC5D, FcRH5 ...
• Use of CAR-T cells in earlier lines of treatment to optimize the immune fitness:
- KarMMa-3, CARTITUDE-4
• Combination therapies with CAR-T cells:
- Gamma-secretase, IMiDs/CELMoDs, immune checkpoint inhibitors
• Improve expansion and reduce risk of toxicities:
- Suicide genes/safety switches as a means to deactivate CAR-T cells, gene editing (e.g. PD-1 knockdown, Select CD4:CD8 ratios
• Sequence of immunotherapies: better understanding of the immune mechanism of resistance
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This year's meeting covered a wide range of topics. In turn, VJHemOnc did interviews on the following topics such as deep science, translational, clinical and commercial development in the field of CAR-T. See these posts on the VJHemOnc events page