Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies
Abstract
:1. Introduction
2. Hit the Road JAK: JAK-STAT Signaling at the Dangerous Crossroads between Inflammation and Clonal Myeloproliferation
3. Tainted Neighborhood: The Emerging Role of the Bone Marrow Niche
4. The Perfect Storm: Combining Inflammation and Specific Mechanisms of Tumor Immune Escape
5. Novel Mutant Hunters: The Emergence of JAK2/CALR Mutation-Targeted T Cell Immunity
6. Looking for the Achilles’ Heel in MPNs: Innovative Targeted Therapies
6.1. Targeting the Microenvironment
6.2. Targeting CD123
6.3. Checkpoint Inhibitors
6.4. Vaccination
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Drug | Target (Mechanism) | Condition(s) | Trial (Phase) | Reference | Results/Comments |
---|---|---|---|---|---|
PRM-151 | Recombinant human pentraxin-2 | MF | NCT01981850 (Phase II) | Verstovsek et al., 2019 [157] | ↓fibrosis, ↓transfusions, only modest SI |
Fresolimumab (GC1008) | TGF-β (MoAb) | MF | NCT01291784 (Phase I) | Mascarenhas et al., 2014 [167] | Only 3 patients enrolled; early termination |
Sotatercept (ACE-011) | TGF-β (ligand trap) | MF with anemia | NCT01712308 (Phase II) | Bose et al., 2016 [164] | ±ruxolitinibEndpoint: ↑Hb ORR (monotherapy) = 35% |
Luspatercept (ACE-536) | TGF-β (ligand trap) | MF with anemia | NCT03194542 (Phase II) | Gerds et al., 2019 [165] | ±ruxolitinibEndpoint: ↑Hb ORR (monotherapy) = 20% |
AVID200 | TGF-β1/β3 (ligand trap) | MF | NCT03895112 (Phase I/Ib) | Still recruiting; no results published yet | |
Galunisertib (LY2157299) | ALK5 (kinase inhibitor) | MF | Preclinical | Yue et al., 2017 [168] | Murine models only: ↓fibrosis |
Alisertib(MLN8237) | AURKA (kinase inhibitor) | MF (or AMKL) | NCT02530619 (Phase I) | Gangat et al., 2019 [153] | SVR = 29%, TI = 8%, SI = 23%, ↓fibrosis |
Bomedemstat (IMG-7289) | LSD1 (small molecule inhibitor) | MF | NCT03136185 (Phase II) | Pettit et al., 2019 [156] | Still recruiting; interim results: SI, slight SVR in a subset of patients |
Mirabegron | β-3 adrenergic agonist | JAK2V617F+ MPNs | NCT02311569 (Phase II) | Drexler et al., 2019 [170] | ↑nestin + MSCs, mild ↓fibrosis, ↓MK clusters, ↔ JAK2V617F allele burden |
Simtuzumab (GS-6624) | LOXL2 (MoAb) | MF | NCT01369498 (Phase II) | Verstovsek et al., 2017 [174] | ±ruxolitinib ↓Fibrosis in 36.7%; limited overall efficacy |
GANT61 | Gli1/Hedgehog (small molecule inhibitor) | MF | Preclinical | Schneider et al., 2017 [88] | Murine and human in vitro models: ↓fibrosis, ↓myofibroblastic phenotype |
Drug | Target (Mechanism) | Condition(s) | Trial (Phase) | Reference | Results/Comments |
---|---|---|---|---|---|
Tagraxofusp (SL-401) | CD123 (MoAb) | MF (or CMML) | NCT02268253 (Phase I/II) | Pemmaraju et al., 2019 [188] | Still recruiting; SVR = 53%, SI = 45% |
Nivolumab | PD-1 (MoAb) | MF | NCT02421354 (Phase II) | - | Terminated early for lack of efficacy |
Pembrolizumab | PD-1 (MoAb) | PV, MF | NCT03065400 (Phase II) | Cimen Bozkus et al., 2019 [131] | Ongoing; ↑reactivity to CALR mutant epitopes in vivo and in vitro |
Durvalumab | PD-L1 (MoAb) | MF | NCT02871323 (Phase I) | Withdrawn before patients’ enrolment | |
Ipilimumab * | CTLA-4 (MoAb) | MPNs (among other conditions) | NCT01822509 (Phase I/Ib) | Ongoing; aims: assessment of AEs and best dose of ipilimumab or nivolumab | |
CALRLong36 peptide (exon 9 mut) vaccine | Mutated CALR (vaccine) | CALR+ PMF and ET | NCT03566446 (Phase I) | Aims: assessment of AEs and T cell cytokine release against the target antigen | |
PD-L1Long (19–27) ArgLong2 (169–206) vaccine | PD-L1 and ARG1 (vaccine) | ET, PV | NCT04051307 (Phase I/II) | Expected effects: ↑specific T cell responses, ↑killing of mutant cells, ↓ARG1, ↓PD-L1 |
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Nasillo, V.; Riva, G.; Paolini, A.; Forghieri, F.; Roncati, L.; Lusenti, B.; Maccaferri, M.; Messerotti, A.; Pioli, V.; Gilioli, A.; et al. Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies. Int. J. Mol. Sci. 2021, 22, 1906. https://doi.org/10.3390/ijms22041906
Nasillo V, Riva G, Paolini A, Forghieri F, Roncati L, Lusenti B, Maccaferri M, Messerotti A, Pioli V, Gilioli A, et al. Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies. International Journal of Molecular Sciences. 2021; 22(4):1906. https://doi.org/10.3390/ijms22041906
Chicago/Turabian StyleNasillo, Vincenzo, Giovanni Riva, Ambra Paolini, Fabio Forghieri, Luca Roncati, Beatrice Lusenti, Monica Maccaferri, Andrea Messerotti, Valeria Pioli, Andrea Gilioli, and et al. 2021. "Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies" International Journal of Molecular Sciences 22, no. 4: 1906. https://doi.org/10.3390/ijms22041906