Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma
Abstract
:1. Introduction
2. The Epidemiological, Immunogenetic and Environmental Background of Hodgkin Lymphoma
3. Pathophysiological Background
3.1. Origin and Molecular Landscape of Malignant Cells in Hodgkin Lymphoma
3.2. Microenvironmental Interactions
3.3. Mechanisms of Resistance
4. Management of Relapsed/Refractory Hodgkin Lymphoma
4.1. The Evolving Place of Brentuximab Vedotin
4.2. Targeting the PD-1 Axis
4.2.1. Nivolumab
4.2.2. Pembrolizumab
4.2.3. Other Investigational Anti-PD-1 Inhibitors
4.3. Novel Agents Potentially Effective in R/R HL
4.3.1. Role of Allogeneic Stem Cell Transplantation
Agent | Mechanism of Action | NCT | Phase | Study Design | Number of Therapeutic Lines | Start Date/Status | Reference | Results if Available |
---|---|---|---|---|---|---|---|---|
Anti-PD-1/PD-L1 | ||||||||
PENPULIMAB | Monoclonal antibody (anti-PD-1) | NCT05244642 | III | Randomized, Open, Multi-center Phase III Study to Evaluate the Efficacy and Safety of Penpulimab Monotherapy vs. Standard Chemotherapy Selected by Investigator | ≥2, relapsed after ASCT | February 2022/Recruiting | Not available | |
CAMRELIZUMAB (SHR-1210) vs. Chemotherapy | Monoclonal antibody (anti-PD-1) | NCT04342936 | III | Open-label, multicenter, randomized trial to evaluate the efficacy of Camrelizumab monotherapy or chemotherapy | ≥2, relapsed after ASCT | July 2020/Recruiting | Not available | |
TISLELIZUMAB | Monoclonal antibody (anti-PD-1) | NCT03209973 | II | Single Arm, Multicenter, Phase 2 Study of BGB-A317 as Monotherapy in R/R cHL | Relapsed after ASCT | July 2017/Completed | Song et al. Leukemia 2020 [123] | ORR:87%; CR: 63% |
TISLELIZUMAB | Monoclonal antibody (anti-PD-1) | NCT04318080 | II | Multicenter, Open-Label Study to evaluate the efficacy of Tislelizumab (BGB-A317) in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma | Relapsed after ASCT | August 2020/Active Not recruiting | Not available | |
TISLELIZUMAB | Monoclonal antibody (anti-PD-1) | NCT04486391 | III | Multicenter, open-Label, randomized Controlled Phase 3 Study of Tislelizumab Monotherapy Versus Salvage Chemotherapy | ≥2, relapsed after ASCT | September 2020/Recruiting | Not available | |
Immunotherapy associations | ||||||||
IPILIMUMAB +/− Nivolumab | Monoclonal antibodies (anti-CTLA-4, anti-PD-1) | NCT04938232 | II | Open-label, multi-cohort, multi-center of ipilimumab with or without nivolumab. | ≥2 including PD-1 monoclonal antibody, relapsed after ASCT | September 2021/Recruiting | Not available | |
Brentuximab Vedotin and Nivolumab with or without IPILIMUMAB | Monoclonal antibodies (anti-CD-30, anti-PD-1, anti-CTLA4) | NCT01896999 | I/II | Randomized Phase II Study of the Combinations of Ipilimumab, Nivolumab and Brentuximab Vedotin. | ≥1 | July 2013/Recruiting | Diefenbach et al. Lancet Haematol 2020 [132] | n = 64; (I) BV + Ipilimumab: ORR= 76%; CR = 57%; (II) BV+ nivolumab ORR = 82%; CR = 61%; (III) BV + Ipilimumab + nivolumab: ORR = 82%; CR = 73% |
MAGROLIMAB and Pembrolizumab | Monoclonal antibodies (anti-CD47, anti-PD-1) | NCT04788043 | II | A Phase 2 Study of Magrolimab and Pembrolizumab | ≥2 | June 2022/Recruiting | Not available | |
CAMRELIZUMAB (SHR-1210) Alone or in Combination with Decitabine | Monoclonal antibody (anti-PD-1) | NCT03250962 | II | Multicohort, decitabine-plus-SHR1210 single-arm clinical trial. Evaluate the long-term response duration with decitabine-plus-SHR-1210 | ≥4, ≥3 months from ASCT | September 2017/Recruiting | Liu et al. J Immunother Cancer 2021 [133] | n = 61; I) SHR-1210: CR= 32%; II) SHR-1210 + decitabine: CR = 79% |
CAMRELIZUMAB (SHR-1210) Combined With GEMOX | Monoclonal antibody (anti-PD-1) | NCT04239170 | II, III | Open-label, single arm, Phase 2 study to evaluate efficacy and safety of PD-1 inhibitor Camrelizumab(SHR-1210) combined with Gemox who will receive ASCT | ≥3, relapsed after ASCT | January 2020/Recruiting | Not available | |
Nivolumab with RUXOLITINIB | Monoclonal antibody (anti-PD-1), JAK2 inhibitor | NCT03681561 | II | Multicenter, open-label, dose escalation/dose-expansion study to evaluate the tolerability, safety, and the maximum tolerated dose (MTD) of ruxolitinib when given with fixed dose nivolumab | ≥2, including check point inhibitors | 13 September 2018/Recruiting | Not available | |
Bispecific Antibody | ||||||||
AZD7789 | Bispecific Antibody (Anti-PD-1 and Anti-TIM-3) | NCT05216835 | I/II | Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD778 | ≥2, no previous treatment with anti-TIM-3 | 18 March 2022/Recruiting | Not available | |
Phase 1 (Part A) Dose Escalation and Phase 2 (Part B) Dose Expansion | ||||||||
Other immunomodulating agents | ||||||||
ITACITINIB (INCB039110) and EVEROLIMUS (Afinitor) | JAK 1 inhibitor; mTOR inhibitor | NCT03697408 | I/II | Open-label, single-group, study of itacitinib in combination with everolimus | ≥2, relapsed after ASCT | 11 February 2019/Recruiting | Not available | |
CAR T-cells | ||||||||
CART30 cells | Autologous CART-30 cells | NCT02259556 | I/II | CD30-directed Chimeric Antigen Receptor T (CART30) Therapy | ≥2 or relapsed after ASCT | October 2014/Recruiting | Not available | |
HSP-CAR30 | Autologous CART-30 cells | NCT04653649 | I/IIa | Interventional, single arm, open label, treatment study to evaluate the safety, tolerability and efficacy of HSP-CAR30 | Relapsed after ASCT who have received anti PD-L1 or Brentuximab; or Primarily refractory patients who do not reach CR after rescue | September 2020/Recruiting | Caballero et al., EHA 2022 | Preliminary results: n = 11; ORR = 100%; CR = 62% |
ATLCAR.CD30 cells | Autologous CART-30 cells | NCT02690545 | Ib/II | Establish a safe dose of ATLCAR.CD30 cells to infuse after lymphodepleting chemotherapy and evaluate relative toxicities | ≥2, CD30+ disease | August 26, 2016/Recruiting | Ramos et al. JCO 2020 [134] | n = 41; CRS = 26%; ORR = 72%; CR = 59%; 1-year PFS = 36%; 1-year OS = 94% |
4.3.2. The Dilemma of Immune Checkpoint Inhibitors before Allo-HCT
4.4. Chimeric Antigen Receptor T Cells in Hodgkin Lymphoma
Design | Anti-PD-1 Molecule | Disease | N# of Patients Receiving Anti-PD-1 before Allo-HCT | Median Time of Anti-PD-1 before Transplant | GvHD Prophylaxis Type | Graft Source | II-IV Grade Acute GvHD | Chronic GvHD | OS | Relapse | NRM | Translational Findings if Available | Reference |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Retrospective | Nivolumab and Pembrolizumab | HL/NHL | 39 | 62 (7–260) | Heterogeneous | BM and PBSC | 44% | 41% | 89% at 1 year | 14 at 1 year | 11 at 1 year | depletion of PD-1+ T cells and reduction in T-reg cells | Merryman et al. Blood 2017 [139] |
Retrospective (subanalysis) | Nivolumab | HL | 11 of 75 pts | 30 (15–190) | Heterogeneous | BM and PBSC | 3 of 11 pts. | 1 of 11 pts. | 10 of 11 pts alive | None | 1 of 11 pts. | NA | Beköz et al. Ann Oncol. 2017 [147] |
Retrospective | Nivolumab, Pembrolizumab, Ipilimumab | HL/NHL/MDS/AML | 14 (N. HL = 10) | 42 (18–231) | PT-Cy, CNI and MMF | BM (n = 12) and PBSC (n = 2) | 6 of 14 pts | None | 13 of 14 pts alive | 2 pts (none with HL) | None | NA | Schoch et al. Blood adv. 2018 [148] |
Retrospective | NA | HL | 37 of 105 pts | 51 (23–472) | PT-Cy, CNI and MMF | BM (n = 31), PBSC (n = 5), CB (n = 1) | 33% | 3% | 94% at 3 years | 4% at 3 years | 6% at 3 years | NA | Paul et al. BBMT 2020 [142] |
Retrospective | Nivolumab | HL/NHL/MM | 18 | 83 (34–154) | CNI/PT-Cy-CNI -MMF | NA | 3 pts receiving CNI alone none of the pts receiving PT-Cy | None | 11 of 18 | 3 of 18 pts | 5 of 18 pts | Circulating nivolumab found in plasma for up to 56 days after allo-HCT and binding PD-1 on T cells inducing T cell activation. Ratio T-reg/CD8: reduced in CNI group and increased in PT-Cy group | Nieto et al. Leukemia 2020 [140] |
Retrospective (subanalysis) | Nivolumab | HL | 39 of 74 | 58 (15–173) | Heterogeneous | BM (n = 2), PBSC (n = 37) | 33% | 35% | 72% at 2 years | 11% | 13% | NA | Martinez et al. [141] |
Retrospective | Nivolumab | HL | 9 | 44 (27–100) | Heterogeneous | NA | 8 of 9 pts | 3 of 9 pts | 8 of 9 pts | 1 pt in SD | 1 of 9 pts | NA | El Cheikh et al. BMT 2017 [149] |
Retrospective | Nivolumab and Pembrolizumab | HL | 25 | 59 (23–539) | Heterogeneous | BM (n = 12), PBSC (n = 11), CB (n = 2) | 47% | None | 52% at 1 year | 27% at 1 year | 8% | NA | Ito et al. Int J Hem 2020 [150] |
5. Age Related Considerations
6. Conclusive Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Hazane Leroyer, E.; Ziegler, C.; Moulin, C.; Campidelli, A.; Jacquet, C.; Rubio, M.T.; Feugier, P.; Pagliuca, S. Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma. J. Clin. Med. 2022, 11, 6574. https://doi.org/10.3390/jcm11216574
Hazane Leroyer E, Ziegler C, Moulin C, Campidelli A, Jacquet C, Rubio MT, Feugier P, Pagliuca S. Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma. Journal of Clinical Medicine. 2022; 11(21):6574. https://doi.org/10.3390/jcm11216574
Chicago/Turabian StyleHazane Leroyer, Esther, Caroline Ziegler, Charline Moulin, Arnaud Campidelli, Caroline Jacquet, Marie Thérèse Rubio, Pierre Feugier, and Simona Pagliuca. 2022. "Filling the Gap: The Immune Therapeutic Armamentarium for Relapsed/Refractory Hodgkin Lymphoma" Journal of Clinical Medicine 11, no. 21: 6574. https://doi.org/10.3390/jcm11216574