Abstract 3476: A single intratumoral injection of IL-12 bound to mesoporous silica rods generates effective anti-tumor immune responses and tumor growth control in multiple syngeneic tumor models

Author: Doherty, Edward ; Seiler, Benjamin ; Pierce, Robert ; Mandley, Everton ; Barra, Brena ; McDonough, Jessica ; Langellotto, Fernanda

AbstractBackground:Interleukin-12 (IL-12) is a potent inflammatory cytokine, which demonstrated anti-tumor activity in both experimental model systems and in a number of clinical trials. Unfortunately, the development of IL-12 as a therapeutic is hampered by severe toxicity in the event of significant systemic exposure. Therefore, intralesional IL-12 therapy has been actively pursued for intratumoral therapy. When delivered into the TME, IL-12 increases intratumoral interferon-γ expression leading to conversion of myeloid cells from an immunosuppressive state into an immunogenic one, recruits CXCR3+ NK and effector T cells, upregulates antigen presentation/processing machinery, and generates anti-tumor immunity. Mesoporous silica rods [MSRs] are currently in development as a modular localized therapeutic platform, due to their large payload capacity, slow-release kinetics, high biocompatibility and intrinsic proinflammatory nature. In this study, we evaluated the anti-tumor effect of MSR plus IL-12 [ATT-02] as an “in situ” (“antigen-less”) vaccine and characterized the immune effects of MSR alone and in in combo with IL-12.Methods:Syngeneic mouse models [B16F10, B16-OVA, CT26, and EMT-6] were conducted by challenging the mice with tumor cells on one flank. Tumors were treated one time with ATT-02 i.t. [Murine IL-12, MSR] when tumors reached the target size. Abscopal models were conducted by injecting tumor cells [CT26, B16F10, and B16-OVA] on both flanks at day zero. The tumor on one flank was treated when it reached the target size. Lymph nodes and spleens were collected at day 7 and analyzed by flow cytometry. In vitro work was conducted by co-culturing MSRs with THP-1 cells that had been initially polarized to an “M2” like phenotype. Repolarization (“M2 to M1”) and APC functionality of THP-1 cells were assayed using flow cytometric phenotyping and proliferation of co-cultured antigen-specific T- cells.Results:ATT-02 i.t. generated potent anti-tumor immunity compared to PBS and IL-12 alone in 3 single tumor syngeneic models and 3 abscopal syngeneic models. Complete responses [CRs] were observed in the CT26 and EMT-6 model after a single dose of ATT-02. Upon rechallenge no tumor growth was observed. In the B16-OVA group, SIINFEKL+ T cells and CD86+ macrophages were observed at a higher level than controls in the draining lymph node of ATT-02 treated mice. Interestingly, MSR i.t. alone resulted in delayed tumor progression the B16F10 model. In vitro, we demonstrated that MSR alone results in a repolarization of macrophages to an immunogenic phenotype capable of driving T cell activation. Addition of IL-12 enhances this effect.Conclusions:I.t. injection of ATT-02 (MSR_IL-12) leads to significant anti-tumor immune responses, antigen-specific responses, and tumor growth inhibition in multiple syngeneic tumor models.Citation Format:Fernanda Langellotto, Jessica McDonough, Everton Mandley, Benjamin Seiler, Brena Barra, Edward Doherty, Robert Pierce. A single intratumoral injection of IL-12 bound to mesoporous silica rods generates effective anti-tumor immune responses and tumor growth control in multiple syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3476.

21 Apr 2025·Cancer Research

Abstract 3467: Delivery of CpG and GM-CSF in a novel silica-based scaffold leads to differentiation of AML blasts and T cell-dependent immunity in syngeneic AML tumor models

Author: Barra, Brena ; Pierce, Robert ; Seiler, Benjamin ; McDonough, Jessica ; Doherty, Edward ; Langellotto, Fernanda

AbstractBackground:Acute Myeloid Leukemia (AML) has poor prognosis, however, differentiation therapy results in a high cure rate for a subset of patients with acute promyelocytic leukemia. Prior preclinical studies using a cryogel-based “antigen free” system demonstrated complete remission in AML models and a vaccine-like response. We set out to recapitulate these effects using a silica-based, biodegradable scaffold (mesoporous silica rod, MSRs) in order to capitalize on their ease of manufacturing and injectability. Building on this prior work, here we show that MSRs loaded with GM-CSF and CpG (ATT-01) can similarly induce differentiation of AML blasts in vitro, a significant vaccine-like T cell response, and durable remission in murine models of AML.Methods:Syngeneic mouse models [C1498, C1498-eGFP, and WEHI-3] were conducted by injecting tumor cells into the mouse tail vein. Tumors were treated with chemotherapy (ara-C, doxorubicin) on days 7-12 and then mice were treated with a subcutaneous injection of ATT-01 on 2 flanks on day 14. For takedown studies, flow cytometry was conducted on mouse organs on day 7 and 14 post-ATT-01 treatment. In a cellular depletion experiment, mice were treated with antibodies to decrease CD8+T-cells, CD4+T-cells and NK cells prior to running the C1498 therapeutic model. In vitro experiments were conducted by co-culturing MSRs with THP-1 cells and tumor cells, and APC functionality of THP1 cells (no PMA) were assayed using flow cytometric phenotyping.Results:Chemotherapy plus ATT-01 treatment resulted in complete remissions [CRs] in C1498 and WEHI-3 models, compared to chemotherapy or GM-CSF and CpG injection alone, which resulted in no CRs. The cellular depletion study demonstrated that CD8+ T cells were required for the therapeutic effect. The takedown study demonstrated that ATT-01 therapy resulted in increased CD8+ T cells in the bone marrow at day 7, compared to controls. In vitro, MSR and ATT-01 caused NETosis in THP-1 cells. In vitro studies demonstrated that Murine AML cell lines cultured with ATT-01 and MSR resulted in tumor cell death for a portion of cells. Surprisingly, a subset of murine AML cell lines expressed immune cell markers after culture with ATT-01 or MSR. In addition, THP-1 cells (human leukemic cell line, no PMA) cultured with MSR and ATT-01 differentiated into immune phenotypes.Conclusions:Treatment of murine AML with chemotherapy and ATT-01 resulted in durable remissions. We propose that generating peripheral inflammation in AML can lead to differentiation of AML blasts into APCs and presentation of AML antigens, leading to immune-mediated tumor control. Future experiments will further elucidate the differentiation effect of ATT-01 in vivo.Citation Format:Fernanda Langellotto, Jessica McDonough, Benjamin Seiler, Brena Barra, Edward Doherty, Robert Pierce. Delivery of CpG and GM-CSF in a novel silica-based scaffold leads to differentiation of AML blasts and T cell-dependent immunity in syngeneic AML tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3467.

Cancer Immunology Research

First-in-Human Clinical Trial of Vaccination with WDVAX, a Dendritic Cell Activating Scaffold Incorporating Autologous Tumor Cell Lysate, in Metastatic Melanoma Patients

Article

Author: Dranoff, Glenn ; Ritz, Jerome ; Daley, Heather ; Giobbie-Hurder, Anita ; Ranasinghe, Srin ; Adu-Berchie, Kwasi ; Hodi, F. Stephen ; Ott, Patrick A. ; Baginska, Joanna ; Manos, Michael P. ; Doherty, Edward J. ; Lako, Ana ; Weirather, Jason L. ; Mooney, David J. ; Severgnini, Mariano ; Stafford, Alexander ; Pfaff, Kathleen L. ; Thrash, Emily M. ; Yoon, Charles H. ; Rodig, Scott J.

AbstractThe optimal means to prime for effective anti-tumor immunity in a cancer patient remains elusive in the current era of checkpoint blockade. Crafting a strategy to amplify CD8+ T cells while blocking regulatory cells should increase immunotherapy efficacy. Biomaterial carriers have been demonstrated in preclinical studies to amplify the effects of immunomodulatory agents, synergistically integrate the effects of different agents, and concentrate and manipulate immune cells in vivo. In this phase I trial in patients with metastatic melanoma, the cytokine GM-CSF and the innate TLR9 agonist CpG oligonucleotide were admixed with autologous tumor lysate onto a microporous poly-lactide-co-glycolide (PLG) matrix polymer scaffold that achieves precise control over the spatial and temporal release of immunostimulatory agents in vivo. This materials system served as a physical antigen-presenting structure for which dendritic cells and other immune-stimulating cells are recruited and activated (WDVAX). In this first clinical trial of a macroscale biomaterial-based vaccine, WDVAX treatment was found to be feasible and induced immune activation in melanoma patients.

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Drug(Targets)	Indications	Global Highest Phase

ATT-01 ( CSF-2R )	Acute Myeloid Leukemia More	Preclinical
ATT-02 ( IL-12R )	Neoplasms More	Preclinical

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