176MO - ORCA-010 Oncolytic Therapy: Inducing Tumor-Specific Immune Responses and Activation of Tumor Microenvironment in Treatment-Naïve Prostate Cancer

Background

Virus-induced antitumor immune responses are the key success of oncolytic viruses (OV). While clinical studies show immune cell infiltration in tumors after OV treatment, distinguishing anti-viral from anti-tumor responses remains difficult. This study presents immunological data from an ongoing phase I/IIa trial showing that oncolytic adenovirus ORCA-010 activates the tumor microenvironment (TME) and systemic immune responses against tumor-specific antigens.

Methods

The study included newly diagnosed patients with localized prostate cancer. In phase I, patients received a single intraprostatic injection of ORCA-010 (3+3 trial design at increasing doses) with one-year follow-up. In phase IIa, 12 patients received two doses of 1.5x10¹² vp of ORCA-010, two weeks apart. Three patients underwent a second biopsy after one year, and nine high-risk patients had radical prostatectomy within two months of the second injection. Biopsies, prostatectomy, and blood samples were analyzed for immune cell changes and tumor-specific T cells.

Results

No dose-limiting toxicities or severe adverse events occurred with either single or repeated doses. Immunobiological analysis showed a shift from an immunologically cold state in pre-treatment biopsies to a hot TME in radical prostatectomy and one-year biopsies, with a rise in CD8+ and CD4+ T cells (up to 2000 cells/mm²). PD-1 and Granzyme B-expressing T cells increased, while regulatory T cells stayed unchanged. Peripheral blood analysis showed an increase in HLA-DR+ and Ki67+ CD8+ T cells within weeks of ORCA-010 injection. CD4+ and CD8+ T cells reactive to prostate antigens emerged post-treatment, declining after radical prostatectomy, supporting the anti-tumor nature of these cells.

Conclusions

Intraprostatic administration of ORCA-010 in prostate cancer patients was safe and induced local and systemic anti-tumor immune responses. The increase in tumor-infiltrating and circulating prostate-specific T cells, along with stable regulatory T cells, indicates a favorable immune environment. These findings suggest that ORCA-010 can convert cold tumors into immunogenic ones, highlighting its promise for prostate cancer immunotherapy.

Clinical trial identification

NCT04097002.

Legal entity responsible for the study

ORCA Therapeutics B.V.

Funding

ORCA Therapeutics B.V.

Disclosure

T.D. de Gruijl: Financial Interests, Institutional, Advisory Board: LAVA Therapeutics, DCPrime, Macrophage Pharma, GE Health; Financial Interests, Personal, Advisory Board: Partner Therapeutics; Financial Interests, Personal, Stocks/Shares: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Immunoglobulins binding human Vγ9Vδ2 T cell receptors; P31885NL00; LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Single domain antibodies targeting CD1d; P32016NL00; EP16715360.0-1412; LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Novel bispecific antibodies for use in the treatment of haematological malignancies. WO/2020/060406, PCT/NL2019/050625; LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Novel CD40 binding antibodies; WO/2020/159368; PCT/NL2020/050051: LAVA Therapeutics; Financial Interests, Personal, Advisory Board, Patent: Recombinant replication competent viruses comprising a coding region for glycogen synthase kinase- (GSK3) and methods of killing aberrant cells. WO/2020/046130, PCT/NL2019/050562: ORCA Therapeutics; Financial Interests, Institutional, Coordinating PI, Research funding from Idera Pharmaceuticals for an investigator-initiated clinical trial (INTRIM) on the intra-dermal administration of IMO-2125 CpG in early-stage melanoma: Idera Pharmaceuticals; Financial Interests, Institutional, Research Grant, Contract research with Macrophage Pharma Inc.” Pre-clinical testing of the immune modulating effects of MPL-5821 in the tumor microenvironment”: Macrophage Pharma; Non-Financial Interests, Personal, Leadership Role, Member of the Board of Directors: SITC, Society for the Immunotherapy of Cancer (SITC); Non-Financial Interests, Personal, Advisory Role, Member of the grant review committee: MRA; Non-Financial Interests, Personal, Advisory Role, Member of their scientific grant reviewing committee: KWF; Non-Financial Interests, Institutional, Product Samples, Provision of Durvalumab for a clinical trial: AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Provision of nivolumab for clinical trials: BMS; Non-Financial Interests, Institutional, Product Samples, Provision of Pembrolizumab for clinical trials: Merck; Non-Financial Interests, Institutional, Product Samples, Anti-CTLA4/PD-1 for clinical trial conduct: Agenus; Non-Financial Interests, Personal, Member: AACR. R. Nadafi, T. Brachtlova, W. Dong, V.W. van Beusechem: Financial Interests, Institutional, Full or part-time Employment: ORCA Therapeutics B.V. All other authors have declared no conflicts of interest.