Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with multiple myeloma

Nandakumar Packiriswamy,Rehan Khan,Stephen J Russell,Angela Dispenzieri,Kah-Whye Peng,Yumei Zhou,Cliona M Rooney,Rosa M Diaz,Amber Miller,Deepak Upreti

doi:10.1038/s41375-020-0828-7

Nandakumar Packiriswamy, Rehan Khan + Show 8 more

Open Access

https://doi.org/10.1038/s41375-020-0828-7

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Abstract

Oncolytic virus therapy leads to immunogenic death of virus-infected tumor cells and this has been shown in preclinical models to enhance the cytotoxic T-lymphocyte response against tumor-associated antigens (TAAs), leading to killing of uninfected tumor cells. To investigate whether oncolytic virotherapy can increase immune responses to tumor antigens in human subjects, we studied T-cell responses against a panel of known myeloma TAAs using PBMC samples obtained from ten myeloma patients before and after systemic administration of an oncolytic measles virus encoding sodium iodide symporter (MV-NIS). Despite their prior exposures to multiple immunosuppressive antimyeloma treatment regimens, T-cell responses to some of the TAAs were detectable even before measles virotherapy. Measurable baseline T-cell responses against MAGE-C1 and hTERT were present. Furthermore, MV-NIS treatment significantly (P < 0.05) increased T-cell responses against MAGE-C1 and MAGE-A3. Interestingly, one patient who achieved complete remission after MV-NIS therapy had strong baseline T-cell responses both to measles virus proteins and to eight of the ten tested TAAs. Our data demonstrate that oncolytic virotherapy can function as an antigen agnostic vaccine, increasing cytotoxic T-lymphocyte responses against TAAs in patients with multiple myeloma, providing a basis for continued exploration of this modality in combination with immune checkpoint blockade.

Highlights

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal expansion of bone marrow plasma cells
To assess the basal T-cell responses of patient-derived Peripheral blood mononuclear cell (PBMC) to ten selected tumor-associated antigens (TAAs), PBMC samples collected before virotherapy were compared with healthy volunteer PBMC samples using IFNγ enzyme-linked immunospot (ELISPOT) assay
In the ten myeloma patients analyzed, T-cell responses against MAGE-C1 and hTERT were detected in 80% of subjects; against NY-ESO-1 in 70%, MAGE-A3 in 50%, PRAME and SSX2 in 30%, p53 in 2, and WT-1 in only 10%

Summary

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Multiple myeloma (MM) is a hematologic malignancy characterized by clonal expansion of bone marrow plasma cells. Oncolytic virotherapy provides a platform to target TAAs by mediating the inflammatory killing of infected myeloma cells, promoting the phagocytosis and cross presentation of released cellular proteins by tumor-resident antigen-presenting cells, and thereby. Oncolytic measles virus therapy enhances tumor antigen-specific T-cell responses in patients with. We recently completed a Phase 1 dose escalation study evaluating the safety and maximal tolerated dose (MTD) of intravenous administration of a single dose of MV-NIS in patients with heavily pretreated relapsed refractory MM [14]. One patient achieved a complete remission and less durable decreases in myeloma-specific IgG and/or serum free light chain (FLCs) levels were seen in other patients. We investigated if MM patients receiving a single intravenous MV-NIS infusion had preexisting T-cell responses against ten different shared tumor antigens, and whether MV-NIS virotherapy enhanced their cytotoxic T-cell responses against these TAA

Materials and methods

Results

Discussion

Compliance with ethical standards