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Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies.

ABSTRACT: CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.

SUBMITTER: Olejarz W

PROVIDER: S-EPMC10741639 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies.

Olejarz Wioletta W Basak Grzegorz G

Cancers 20231208 24

CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ severa ...[more]

PMID: 38136311

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Project description:BackgroundAcute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance.Methods/designThe trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy.DiscussionCellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome.Trial registrationNCT01685606.

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Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies.

Publications

Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies.

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