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Clinical Trial
. 2020 Dec;34(12):3310-3322.
doi: 10.1038/s41375-020-0828-7. Epub 2020 Apr 23.

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

Nandakumar Packiriswamy  1 , Deepak Upreti  1 , Yumei Zhou  1 , Rehan Khan  2 , Amber Miller  1 , Rosa M Diaz  3 , Cliona M Rooney  4 , Angela Dispenzieri  2 , Kah-Whye Peng  1   3 , Stephen J Russell  5   6   7
Affiliations
Clinical Trial

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

Nandakumar Packiriswamy et al. Leukemia. 2020 Dec.

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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Patients with multiple myeloma react against tumor-associated antigens (baseline).
a T-cell responses against ten tumor-associated antigens were compared between a healthy volunteer peripheral blood mononuclear cell (PBMCs) sample and PBMCs from a multiple myeloma patient with use of IFN-γ enzyme-linked immunospot (ELISPOT). The numbers of spots are listed above each well. CEF peptide pool was used as a positive control. TNTC indicates too numerous to count. b T-cell responses against MAGE-C1, hTERT, NY-ESO-1, and MAGE-A3 were significantly increased in patient PBMC samples (n = 10) compared with healthy volunteer PBMC samples (n = 10). Gray-shaded area denotes limit of negative response. c Heatmap showing fold change of TAA gene expression in CD138+ cells from MM patients (n = 3) compared with healthy volunteers (n = 5). Gene expression normalized to GAPDH.
Fig. 2
Fig. 2. MV-NIS virotherapy induces increased T-cell reactivity against MAGE-C1 and MAGE-A3.
a Of the ten tumor-associated antigens, T-cell responses against MAGE-C1 and MAGE-A3 were significantly increased in patient peripheral blood mononuclear cell samples after measles virus-sodium iodide symporter (MV-NIS) virotherapy. (n = 10). Gray-shaded area denotes the limit of negative response. b Representative image showing increased IFN-γ responses against MAGE-C1, MAGE-A1, and MUC-1 at 6 weeks after MV-NIS virotherapy. CEF peptide pool was used as a positive control. Sole asterisk indicates P < 0.05, double asterisks, P < 0.01; triple asterisks, P < 0.001, compared with the corresponding groups. Error bars indicate mean with standard error of mean. CEF indicates CEF-positive control peptide pools; CT/DMSO control/dimethylsulfoxide, IFN interferon.
Fig. 3
Fig. 3. T-cell responses and mutational load in complete responder (CR) patient.
a Complete remission patient, T-cell responses to most TAAs were detected pre and 6 weeks post virotherapy. b Serum FLC levels and Immunoglobulin (IgG) post-virotherapy in CR patient. FLC, free light chain; c Comparison of exome sequencing data on CR patient tumor and PBMCs samples revealed 530 somatic missense mutations. The patient in complete remission had a greater mutational load than a subset of 664 MM patients representing the CoMMpass population from the interim data of the Multiple Myeloma Research Foundation CoMMpass Study (NCT 01454297). d Functional validation of neoantigens using IFNγ ELISPOT revealed no T-cell response to the predicted 68 neoantigens. Neoantigens were pooled based on their physicochemical properties and tested for T-cell reactivity on 6 week post virotherapy sample. Each of the respective groups (A, B, C, D) was compared with their respected unstimulated groups and their % fold change is depicted. CEF peptide pool was used as positive control.
Fig. 4
Fig. 4. Identification of distinct T-cell response patterns to TAAs in MM patients after MV-NIS virotherapy.
ELISPOT responses compared with serum FLC and IgG levels. a Partial response patient, T-cell responses to most TAAs were detected postvirotherapy only. This patient had a transient decline in serum FLC levels postvirotherapy. b Nonresponding patient, T-cell responses to TAAs were not detected before or after virotherapy. This patient had no decline in serum FLC levels post-therapy. c Nonresponding patient, T-cell responses to TAAs and CEF peptide pools were not detected before or after virotherapy. This patient had no decline in serum FLC levels post-therapy. CEF peptide pool was used as positive control. CT/DMSO control/dimethylsulfoxide, PRE previrotherapy, TAA tumor-associated antigen.
Fig. 5
Fig. 5. MV-NIS induced measles virus-specific T-cell responses in MM patients.
6 weeks post virotherapy T-cell responses against measles viral hemagglutinin (H), neuraminidase (N), and fusion (F) antigens were significantly higher in nonresponding (b) and partial response patient (c) but not in complete remission patient (a). Adenoviral penton and hexon were used as nonspecific viral antigen control.
Fig. 6
Fig. 6. MV-NIS virotherapy induces changes in circulating CD8+ T cells.
a Stored peripheral blood mononuclear cell samples from both patients and healthy volunteers were immune-phenotyped to determine T-cell percentages. Both %CD3+ and %CD8+ cells were found to be significantly increased in patients postvirotherapy. Complete responder is highlighted in red and partial responder in blue. b Percentages of the T-cell subpopulation based on expression of CCR7 and CD45RA. The number of CD4+ T effector cells was higher in patients before virotherapy. CD8+ T effector memory cells were more numerous among patients after virotherapy and healthy volunteers. CD8+ T central memory decreased in patients before virotherapy compared with healthy volunteers. c Percentages of PD1-expressing CD8+ T cells were greater in patients after virotherapy. Sole asterisk indicates P < 0.05; double asterisks, P < 0.01; triple asterisks, P < 0.001, compared with the corresponding groups. Error bars indicate mean with standard error of mean. Healthy indicates healthy controls; PT Pre patient pretreatment, PT Post patient posttreatment, TCM central memory T cells, TEFF effector T cells, TEM effector memory T cells, TNaïve naïve T cells, Tregs regulatory T cells.
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