BSH 2018: Personalised cancer vaccines and cellular therapy: changing the treatment paradigm for haematological malignancies

Dendritic cells (DC) are known to play an important role in the initiation of primary immune responses. In cancer, deficient DCs contribute to tumour-associated immune tolerance. Functionally active DCs can be grown ex vivo from peripheral blood mononuclear cells in the presence of cytokines and can be made to carry tumour antigens to stimulate an anti-tumour response…

Article by Maria Dalby. Interviews by Esther Drain.

Professor David E Avigan (Boston) and Dr Martin Kaiser (London) highlight the unique promise of immune therapy in the above video.

Novel therapies, including biological agents, have improved outcomes in multiple myeloma (MM) but for most patients the disease remains incurable – it will progress and eventually become resistant. In the concluding UK Myeloma Forum presentation, Professor David Avigan from the Beth Israel Deaconess Medical Center outlined the ongoing work by his team at Harvard Medical School to develop immunotherapeutic strategies for eradicating malignant cells and residual disease following intensive therapy and autologous stem cell transplantation (ASCT). The rationale for these efforts was the observation that allogeneic haematopoietic stem cell transplantation can cure a proportion of patients due to the graft-versus-disease effect.^1-6 However, allogeneic transplantation is associated with significant morbidity and mortality due to the toxicity of the treatment regimens and the high risk of graft-versus-host disease. Professor Avigan’s work is therefore focused on achieving myeloma-specific immune responses that are tumour selective and that generate a memory to prevent recurrence.

Dendritic cells (DC) are known to play an important role in the initiation of primary immune responses.^{7, 8} In cancer, deficient DCs contribute to tumour-associated immune tolerance.⁹ Functionally active DCs can be grown ex vivo from peripheral blood mononuclear cells (PBMCs) in the presence of cytokines^{10, 11} and can be made to carry tumour antigens to stimulate an anti-tumour response.^12-15 Professor Avigan and his team have developed a myeloma vaccine by fusing autologous DCs with myeloma cells. In a Phase 1 study 17 patients, with a mean age of 57 years and a median of four prior lines of therapy, received vaccine doses of 1 × 10⁶ (3 patients), 2 × 10⁶ (4 patients), and 4 × 10⁶ fusion cells (9 patients)  and achieved a 10-fold expansion of myeloma-reactive T-cells, and for the majority of patients (66%) disease stabilisation.¹⁶ A further study has explored DC/MM fusion vaccination in conjunction with autologous transplantation, based on the rationale that the transplantation will minimise the immunosuppressive effect of MM and result in a more durable response.¹⁷ In this study 35 patients received vaccine after ASCT and achieved a post-transplant increase in myeloma-specific T cells that was significantly expanded following vaccination. A total of 78% of patients achieved CR or VGPR, and 47% achieved a CR/nCR; 24% of patients who achieved PR following transplantation were upgraded to CR/nCR after vaccination, indicating a vaccine-mediated effect on residual disease.¹⁷

Professor Avigan also discusses his research into vaccines for myeloma and how these may have synergies with CAR-T cell therapies in the future.

A Phase 2 multicentre study, BMT CTN Protocol 1401, is currently evaluating DC/MM fusion vaccination in combination with lenalidomide maintenance therapy following ASCT, with survival and CR rates at one year post-transplant as the primary clinical endpoint and the expansion of treatment-induced myeloma-specific T cells as a primary immunological endpoint. Another strategy that is being explored for enhancing the efficacy of DC/MM fusion vaccination is combination with chimeric antigen receptor (CAR) T cell therapy. The rationale for this is that combining vaccination with CAR T cells will allow for vaccine-mediated activation and expansion of the CAR-T cells which will yield a broader T cell response and greater persistence. As the complex interactions between the immune system, and the tumour cells and their microenvironment become better understood, the aim is to be able to integrate therapy to not just cure MM but prevent it.

References

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