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FINDING CURES TOGETHER<sup>SM</sup>

AACR-Takeda Oncology Fellowships  

The AACR-Takeda Oncology (formerly Millennium Pharmaceuticals) Fellowships represent a joint effort to promote and support mentored young investigators to conduct lymphoma and multiple myeloma research and to establish successful career paths in these fields. Eligibility is limited to postdoctoral and clinical research fellows who will have completed their most recent doctoral degree within the past five years. The research proposed for funding may be basic, translational, clinical, or epidemiological in nature. 

AACR-Takeda Oncology Fellowships in Multiple Myeloma Research

Barbara Castella, PhD
Postdoctoral Fellow
University of Torino
Torino, Italy
Targeting immune inhibitory pathways in the bone marrow of myeloma patients

Myeloma cells are susceptible to immune recognition and clearance, but daily clinical practice does not fit with this assumption. The immune microenvironment is highly dysfunctional in the bone marrow (BM) of multiple myeloma (MM) patients. These dysfunctions are still present in patients who achieve remission and already detectable in MGUS. Novel immunotherapy approaches are urgently needed in MM with special attention to adoptive immunotherapy with “non-conventional T cells” such as Vγ9Vδ2 (γδ) T cells. They have a natural inclination to recognize and kill malignant B cells through their dual-recognition ability mediated by the T-cell receptor and a peculiar array of NK receptors. Normal γδ T cells can easily be activated and expanded with synthetic and natural phosphoantigens (pAgs), as isopentenylpyrophosphate (IPP), to generate MHC-unrestricted anti-myeloma activity. γδ T cells are therefore very attractive candidates for adoptive immunotherapy in MM though clinical trials with autologous γδ T cells have not met the expectations. Recent data showed that γδ T cells from the BM of MM patients have lost their immune competence and have become anergic to pAg stimulation. They are PD-1+ suggesting a functional exhaustion probably induced by the prolonged exposure to high IPP levels locally generated by myeloma cells and stromal cells. Anti-PD-1 treatment partially reinstates BM γδ T cell reactivity and improves their cytotoxic ability in MM patients. PD-1/PD-lL is not the only immune inhibitory pathway operative in MM. Preliminary results highlight that other ligand/receptor pairs such as TIM-3/GAL-9 and BTLA/HVEM are involved. BM γδ T cells from MM patients display high TIM-3 expression that is further increased after stimulation with pAgs, suggesting that anergic γδ T cells are prone to further up-regulate the expression of immune checkpoint receptors upon ineffective TCR engagement by pAgs. Moreover, the strong expression of BTLA on BM γδ T cells and the up-regulation of its ligand HVEM on myeloma cells represent another inhibitory pathway usable by MM microenvironment to impair anti-tumor immune responses.

The results of this project will help to understand whether checkpoint blockade combinations could be a potentially promising target for cancer immunotherapy in MM patients.

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