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Adoptive T-cell therapy for Hodgkin lymphoma.

ABSTRACT: Although CAR T-cell therapy is US Food and Drug Administration-approved for B-cell non-Hodgkin lymphomas, the development of adoptive immunotherapy for the treatment of classic Hodgkin lymphoma (cHL) has not accelerated at a similar pace. Adoptive T-cell therapy with Epstein-Barr virus-specific cytotoxic T lymphocytes and CD30 CAR T cells have demonstrated significant clinical responses in early clinical trials of patients with cHL. Additionally, CD19 and CD123 CAR T cells that target the immunosuppressive tumor microenvironment in cHL have also been investigated. Here we discuss the landscape of clinical trials of adoptive immunotherapy for patients with cHL with a view toward current challenges and novel strategies to improve the development of CAR T-cell therapy for cHL.

SUBMITTER: Ho C

PROVIDER: S-EPMC8945637 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Adoptive T-cell therapy for Hodgkin lymphoma.

Ho Carrie C Ruella Marco M Levine Bruce L BL Svoboda Jakub J

Blood advances 20211001 20

Although CAR T-cell therapy is US Food and Drug Administration-approved for B-cell non-Hodgkin lymphomas, the development of adoptive immunotherapy for the treatment of classic Hodgkin lymphoma (cHL) has not accelerated at a similar pace. Adoptive T-cell therapy with Epstein-Barr virus-specific cytotoxic T lymphocytes and CD30 CAR T cells have demonstrated significant clinical responses in early clinical trials of patients with cHL. Additionally, CD19 and CD123 CAR T cells that target the immuno ...[more]

PMID: 34610100

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Project description:Background: Interaction of the programmed death receptor 1 (PD-1) and its ligand, PD-L1, suppresses T cell activity and permits tumors to evade T cell-mediated immune surveillance. We have recently demonstrated that antigen-specific CD8+ T cells transduced with a PD1-CD28 fusion protein are protected from PD-1-mediated inhibition. We have now investigated the potential of PD1-CD28 fusion protein-transduced CD4+ T cells alone or in combination with CD8+ T cells for immunotherapy of pancreatic cancer and non-Hodgkin lymphoma. Methods: OVA-specific CD4+ and CD8+ were retrovirally transduced with the PD1-CD28 fusion protein. Cytokine release, proliferation, cytotoxic activity, and phenotype of transduced T cells were assessed in the context of Panc02-OVA (murine pancreatic cancer model) and E.G7-PD-L1 (murine T cell lymphoma model) cells. Results: Stimulation of PD1-CD28 fusion protein-transduced CD4+ T cells with anti-CD3 and recombinant PD-L1 induced specific T cell activation, as measured by IFN-y release and T cell proliferation. Coculture with Panc02-OVA or E.G7-PD-L1 tumor cells also led to specific activation of CD4+ T cells. Cytokine release and T cell proliferation was most effective when tumor cells simultaneously encountered genetically engineered CD4+ and CD8+ T cells. Synergy between both cell populations was also observed for specific tumor cell lysis. T cell cytotoxicity was mediated via granzyme B release and mediated enhanced tumor control in vivo. Transduced CD4+ and CD8+ T cells in co-culture with tumor cells developed a predominant central memory phenotype over time. Different ratios of CD4+ and CD8+ transduced T cells led to a significant increase of IFN-y and IL-2 secretion positively correlating with CD4+ T cell numbers used. Mechanistically, IL-2 and MHC-I were central to the synergistic activity of CD4+ and CD8+ T cells, since neutralization of IL-2 prevented the crosstalk between these cell populations. Conclusion: PD1-CD28 fusion protein-transduced CD4+ T cells significantly improved anti-tumoral effect of fusion protein-transduced CD8+ T cells. Thus, our results indicate that PD1-CD28 fusion protein-transduced CD4+ T cells have the potential to overcome the PD-1-PD-L1 immunosuppressive axis in pancreatic cancer and non-Hodgkin lymphoma.

Project description:Purpose of reviewPeripheral T cell lymphomas (PTCLs) are a heterogeneous group of diseases and represent approximately 10-15% of all non-Hodgkin lymphomas. Multiagent chemotherapy with a CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-like regimen is the current standard of care in the frontline setting, but outcomes for PTCL patients generally remain poor. Strategies used to improve survival and reduce the risk of relapse in PTCL patients include autologous hematopoietic cell transplant (autoHCT) and allogeneic HCT (alloHCT). Due to the relative rarity of these diseases, the evidence supporting the use of autoHCT and alloHCT is based on retrospective and single-arm prospective studies. Novel targeted therapies are now being incorporated into the treatment of PTCL, and they may play important roles in improving upon current standards of care. Herein, we summarize the evidence supporting HCT for the treatment of the most common PTCL histologic subtypes and highlight novel treatment strategies aimed at improving outcomes for these patients, including cutting-edge approaches using chimeric antigen receptor T cells (CAR-T).Recent findingsGiven recent improvements in OS and PFS in CD30+ PTCL using the drug-antibody conjugate brentuximab vedotin (BV), new questions arise regarding the impact of BV on consolidative autoHCT, and its role as a maintenance therapy. Multiple histone deacetylase inhibitors (HDACis) have been approved for the treatment of relapsed/refractory PTCL, and these agents are being incorporated into HCT approaches, both in the frontline and maintenance settings. Early data incorporating these agents into novel conditioning regimens have been reported, and emerging evidence from recent trials suggests that CART cell therapies may prove effective in relapsed/refractory PTCL. The recommended treatment strategy in non-ALK+ PTCL remains induction with a CHOP-like regimen followed by consolidative autoHCT in first remission. In the relapsed/refractory setting, salvage chemotherapy followed by HCT (autoHCT or alloHCT depending on histologic subtype and HCT history) offers the only potential for cure or long-term remission. Ample room for improvement remains in the treatment of patients with PTCL, and novel treatment strategies incorporating targeted agents and CAR-T therapy may help to address the unmet needs of this patient population.

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Adoptive T-cell therapy for Hodgkin lymphoma.

Publications

Adoptive T-cell therapy for Hodgkin lymphoma.

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