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Therapeutic ISCOMATRIX™ adjuvant vaccine elicits effective anti-tumor immunity in the TRAMP-C1 mouse model of
Adele M Barr1, Anabel Silva2, Sandro Prato2
1CSL Limited, Bio21 Institute, 30 Flemington Rd, Parkville, VIC, 3010, Australia. adele.barr@csl.com.au.
Abstract:
Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic-polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™-mPAP-Poly I:C-Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA).
Insights
A novel cancer vaccine combining ISCOMATRIX adjuvant, Poly I:C, and Flt3L achieved complete tumor regression in 60% of mice. This therapeutic approach shows promise for treating prostate cancer and other malignancies.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Cancer vaccine development faces challenges, with few approved treatments, particularly for prostate cancer.
- Prostate cancer represents a significant unmet medical need in cancer therapy.
- Existing prophylactic vaccines are limited to virally induced cancers.
Purpose of the Study:
- To evaluate a novel therapeutic cancer vaccine combining ISCOMATRIX adjuvant, polyinosinic-polycytidylic acid (Poly I:C), and FMS-like tyrosine kinase 3 ligand (Flt3L).
- To assess the vaccine's efficacy in the TRAMP-C1 mouse model of prostate cancer using prostatic acid phosphatase (mPAP) as the tumor antigen.
- To investigate the immunological mechanisms underlying the vaccine's therapeutic effect.
Main Methods:
- Utilized the TRAMP-C1 mouse model for prostate cancer and mPAP as the tumor antigen.
- Administered the ISCOMATRIX-mPAP-Poly I:C-Flt3L vaccine in a therapeutic prime-boost regimen.
- Analyzed immune responses, including NK cells, CD4+ T cells, CD8+ T cells, and interferon-gamma, in tumor-infiltrating lymphocytes and surrounding tissues.
Main Results:
- Achieved complete tumor regression in 60% of treated animals, with durable protection upon rechallenge.
- Demonstrated that both innate (NK cells) and adaptive (CD4+ T cells, interferon-gamma) immune responses are critical for tumor control.
- Observed that tumor-infiltrating CD8+ T cells were impaired by an immunosuppressive tumor microenvironment.
- Showcased potential broader applicability by demonstrating effectiveness in melanoma (B16-OVA) and B cell lymphoma (Eµ-myc-GFP-OVA) models.
Conclusions:
- The novel ISCOMATRIX-mPAP-Poly I:C-Flt3L vaccine is a promising therapeutic strategy for prostate cancer.
- The vaccine elicits robust innate and adaptive immune responses essential for tumor eradication.
- Further research into overcoming the immunosuppressive tumor microenvironment could enhance therapeutic outcomes and broaden vaccine applicability.
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