Development of Novel Immunotherapies for Multiple Myeloma

Al-Hujaily, Ensaf M.; Oldham, Robyn A. A.; Hari, Parameswaran; Medin, Jeffrey A.

doi:10.3390/ijms17091506

Cited by 23 publications

(22 citation statements)

References 216 publications

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“…antigens such as SLAMF7, CD38, CD74, or CD138 39 , providing naturally processed HLA-presented ligands derived from intracellular domains of established membrane-bound tumor-associated antigens. Such HLA ligands represent promising targets for (i) low side effect single agent vaccine approaches in elderly patients or early disease states 21,28,40 , (ii) TCR-engineered T cells 41 , (iii) antibody-based approaches 42 , or (iv) novel approaches combining HLA-dependent and -independent antigens and treatments 43 .…”

Section: Discussionmentioning

confidence: 99%

“…Besides the selection of optimal target antigens for the development of clinically effective T-cell-based immunotherapies in MM, one must consider the profound immune defects that prevail in these patients and might impair the efficacy of inducing antigen-specific T-cell responses in vivo 22,47 . A major immunosuppressive mechanism in MM is the upregulation of inhibitory immune checkpoint molecules on T cells 22,39 . By employing PD-1/CTLA-4 blockade, we were able to overcome this mechanism and to induce multifunctional cytotoxic P(BCMA) B*18 -specific T cells, even in MM-derived samples.…”

Section: Discussionmentioning

confidence: 99%

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Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

et al. 2020

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The B-cell maturation antigen (BCMA) is currently being evaluated as promising tumor-associated surface antigen for T-cell-based immunotherapy approaches, such as CAR T cells and bispecific antibodies, in multiple myeloma (MM). Cytotoxic T cells bearing BCMA-specific T-cell receptors might further allow targeting HLA-presented antigens derived from the intracellular domain of BCMA. By analyzing a mass spectrometry-acquired immunopeptidome dataset of primary MM samples and MM cell lines for BCMA-derived HLA ligands, we identified the naturally presented HLA-B*18restricted ligand P(BCMA) B*18. Additionally, P(BCMA) B*18 was identified on primary CLL samples, thereby expanding the range for possible applications. P(BCMA) B*18 induced multifunctional BCMA-specific cells de novo from naïve CD8 + T cells of healthy volunteers. These T cells exhibited antigen-specific lysis of autologous peptide-loaded cells. Even in the immunosuppressive context of MM, we detected spontaneous memory T-cell responses against P(BCMA) B*18 in patients. By applying CTLA-4 and PD-1 inhibition in vitro we induced multifunctional P(BCMA) B*18-specific CD8 + T cells in MM patients lacking preexisting BCMA-directed immune responses. Finally, we could show antigen-specific lysis of autologous peptide-loaded target cells and even MM.1S cells naturally presenting P(BCMA) B*18 using patient-derived P(BCMA) B*18-specific T cells. Hence, this BCMA-derived T-cell epitope represents a promising target for T-cell-based immunotherapy and monitoring following immunotherapy in B-cell malignancy patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

et al. 2020

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“…To date treatment of MM has focused on stem cell transplantation, targeted agents such as the proteosome inhibitor bortezomib, immune modulation with lenalidomide, and standard and high dose cytotoxic chemotherapies. While many patients benefit from these therapies, relapse is common and new therapies are needed [74,75]. Recent areas of interest include immunotherapies that trigger the host anti-tumor immune response and thus far, the results are promising [75,76].…”

Section: Tam Receptors In Hematopoietic Malignanciesmentioning

confidence: 99%

“…While many patients benefit from these therapies, relapse is common and new therapies are needed [74,75]. Recent areas of interest include immunotherapies that trigger the host anti-tumor immune response and thus far, the results are promising [75,76]. Therapeutic approaches include checkpoint inhibitors, MM vaccines, adoptive T Cell Transfer [77], and monoclonal antibodies.…”

Section: Tam Receptors In Hematopoietic Malignanciesmentioning

confidence: 99%

Targeting the TAM Receptors in Leukemia

Huey

Minson

Earp

et al. 2016

Cancers

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Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

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“…75,76 Used as a single agent, daratumumab had a 36% response rate in patients with refractory myeloma. 77 Drent et al have demonstrated in preclinical work that anti-CD38 CAR-Ts proliferate, produce cytokines, and lyse CD38 1 MM cells; however, these CAR-Ts lysed not only CD38…”

Section: Cd38mentioning

confidence: 99%

Chimeric antigen receptor T-cell therapies for multiple myeloma

Mikkilineni¹,

Kochenderfer

2017

Blood

188

176

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Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte–activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.

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Development of Novel Immunotherapies for Multiple Myeloma

Cited by 23 publications

References 216 publications

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

Targeting the TAM Receptors in Leukemia

Chimeric antigen receptor T-cell therapies for multiple myeloma

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