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The clinical results achieved with immunotherapy in the past few years have now firmly established it within the cancer armamentarium. Our group has explored a novel approach to adoptive T-cell therapy utilizing marrow-infiltrating lymphocytes (MILs) initially developed with the concept of utilizing a population of T cells with a higher endogenous tumor specificity. Marrow-infiltrating lymphocytes are antigen-experienced T cells that home to and remain in the bone marrow (BM) because of the unique biology of the BM microenvironment. Marrow-infiltrating lymphocytes can easily be obtained from the BM and can be expanded to demonstrate enhanced antigen specificity. Current clinical trials utilize MILs for patients with myeloma as well as patients with relapsed disease following an allogeneic transplant. Ongoing preclinical work is currently evaluating MILs for use in solid cancers as well as pediatric cancers. The examination of a MIL as a source cell for chimeric antigen receptor T or transgenic cell receptor is also in the preclinical stages. Until now, for both chimeric antigen receptor T-cell therapy and transgenic cell receptor T-cell therapy, the target cell of choice has included peripheral blood. The unique antigen-experienced properties of MILs may make them the ideal source of cell for gene modification strategies. Therefore, MILs are a distinctive set of T cells that have been shaped by the unique BM microenvironment and may play a future role as a novel immunotherapy for hematologic malignancies. [ABSTRACT FROM AUTHOR]

Despite recent advancement of treatment strategies in multiple myeloma (MM), patients with relapsed/refractory MM disease, particularly after triple-class refractoriness, continue to have poor prognosis. Chimeric antigen receptor (CAR-T) cells were developed and applied to improve outcomes in this setting, and two products, idecabtagene vicleucel and ciltacabtagene autoleucel, both targeting B-cell maturation antigen, have been approved by the Food and Drug Administration in the United States and European Medicines Agency in Europe. Both have shown unprecedented clinical outcomes with high response rate and prolonged progression-free survival and overall survival in this patient population with grim prognosis. Currently, further investigations are ongoing for CAR-T targeting different tumor antigens such as G protein-coupled receptor, class C, group 5, member D or with different combinations of intracellular signaling domains, as well as fourth-generation CAR-T with antigen-unrestricted inducible cytokines. Although CAR-T therapies hold hopes and enthusiasm from the myeloma community, several hurdles remain before these treatments become available for all patients in need. These barriers include CAR-T-cell manufacturing availability, access to administering centers, financial cost, caregivers' availability, and socioeconomic and racial disparities. Expanding clinical trial eligibility criteria and real-world data collection and analysis is crucial to understand the efficacy and safety of CAR-T in the patient cohort who tends to be excluded from current trials.

A better understanding of how solid malignancies arise in an immunocompetent host, avoid immune recognition, and ultimately progress to widely disseminated cancer is essential to effectively harness the immune system against solid tumors. Because of their extra-lymphatic localization, it has been proposed that solid malignancies are just ignored by the immune system, thereby allowing their uncontrolled growth and dissemination. Alternatively, as most of the solid tumors are unable to express costimulatory molecules, the "signal one without signal two" model of tolerance induction has been frequently evoked to account for the failure of the immune system to reject antigenic tumors in vivo. In this study, we showed, however, that the extra-lymphatic growth of solid tumors is not immunologically ignored by the lymphoid compartment, resulting instead in the early induction of antigen-specific CD4(+) T-cell tolerance. Furthermore, analysis of parent-into-F1 bone marrow (BM) chimeras demonstrates that presentation of tumor antigens by BM-derived antigen-presenting cells represents the dominant mechanism in solid tumor-induced CD4(+) T-cell tolerance. Our findings of early development of antigen-specific T-cell unresponsiveness mediated by BM-derived antigen-presenting cells, not only provides a plausible explanation for the failure of the immune system to reject antigenic solid tumors in vivo, but more importantly, they have identified a barrier that, if appropriately manipulated, may lead to approaches to effectively harness the immune system against solid malignancies.