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31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

National Harbor, MD, USA. 9-13 November 2016
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Journal for ImmunoTherapy of Cancer20164(Suppl 1):73

https://doi.org/10.1186/s40425-016-0173-6

Published: 16 November 2016

Combinations: Immunotherapy/Immunotherapy

P189 Rational combinations of intratumoral T cell and myeloid agonists mobilize abscopal responses in prostate cancer

Casey Ager1, Matthew Reilley2, Courtney Nicholas1, Todd Bartkowiak1, Ashvin Jaiswal1, Michael Curran1

1Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Correspondence: Casey Ager (crager@mdanderson.org)

Background

Despite the success of checkpoint blockade immunotherapy in characteristically immunogenic cancers such as melanoma, these antibodies remain ineffective against poorly T cell-infiltrated malignancies including prostate cancer. Sensitizing these “cold” tumors to immunotherapy will require interventions which enhance tumor antigen presentation and T cell priming, while suppressing microenvironmental signals which constrain T cell expansion, survival, and effector function independent of coinhibitory signaling. We investigated whether intratumoral administration of either the STING agonist c-di-GMP (CDG) or dendritic cell (DC) growth factor Flt3-ligand can potentiate the therapeutic effects of T cell checkpoint modulation with αCTLA-4, αPD-1, and α4-1BB in a bilateral subcutaneous model of prostate adenocarcinoma. Additionally, we tested whether intratumoral delivery of low-dose checkpoint modulators with CDG at a single lesion can achieve abscopal control of distal lesions.

Methods

Male C57BL/6 mice were challenged subcutaneously on both flanks with TRAMP-C2 prostate adenocarcinoma, and treatment was administered intraperitoneally and/or intratumorally for 3 doses every 4 days, beginning on day 14 post-implantation for survival experiments or day 31 for flow analysis experiments.

Results

Intratumoral delivery of STING agonist CDG alone potently rejects all injected TRAMP-C2 tumors, but fails to generate systemic control of uninjected lesions. Systemic administration of αCTLA-4, αPD-1, and α4-1BB cures 40 % of mice with bilateral TRAMP-C2, and concurrent administration of CDG at one or both flanks enhances survival to 75 %. Similar effects are observed with intratumoral Flt3L, although administration at both flanks is required for full effect. Intratumoral low-dose αCTLA-4, αPD-1, and α4-1BB at a single flank induces abscopal effects in 20 % of mice, and concurrent administration of CDG enhances systemic immunity to cure up to 50 % of mice. We observe that the level of STING activation required to mediate rejection without inducing ulcerative toxicity is proportional to initial tumor size. Functionally, local STING activation complements intratumoral checkpoint modulation to reduce local MDSC infiltration, enhance CD8:Treg ratios, and downregulate the M2 macrophage marker CD206. In contrast, local Flt3L robustly enhances immune infiltration of injected and distal tumors, but therapeutic benefit is attenuated due to concomitant induction of FoxP3+ Treg.

Conclusions

Intratumoral STING activation via CDG or DC expansion with Flt3L potentiates the therapeutic effects of systemically-delivered αCTLA-4, αPD-1, and α4-1BB against multi-focal TRAMP-C2 prostate cancer. The abscopal potential of CDG alone is weak, in contrast to prior observations, but combining CDG with low-dose checkpoint blockade intratumorally can induce systemic immunity, suggesting an alternative approach for clinical implementation of combination immunotherapies at reduced doses.

P190 Multi-genome reassortant dendritic cell-tropic vector platform (ZVex®-Multi) allows flexible co-expression of multiple antigens and immune modulators for optimal induction of anti-tumor CD8+ T cell responses

Tina C Albershardt, Anshika Bajaj, Jacob F Archer, Rebecca S Reeves, Lisa Y Ngo, Peter Berglund, Jan ter Meulen

Immune Design, Seattle, WA, USA
Correspondence: Tina C Albershardt (tina.albershardt@immunedesign.com)

Background

Induction of immune responses against multiple antigens expressed from conventional vector platforms is often ineffective for reasons not well understood. Common methods of expressing multiple antigens within a single vector construct include the use of fusion proteins, endoprotease cleavage sites, or internal ribosome entry sites. These methods often lead to decreased expression of antigens-of-interest and/or reduced induction of T cell responses against the encoded antigens. Circumventing these limitations, we have developed a novel production process for our integration-deficient, dendritic cell-targeting lentiviral vector platform, ZVex, enabling highly flexible and effective multigene delivery in vivo, making it possibly the most versatile vector platform in the industry.

Methods

Up to five vector genome plasmids, each encoding one full-length antigen or immuno-modulator, were mixed with four constant plasmids, each encoding vector particle proteins, prior to transfection of production cells. Due to the propensity of lentiviruses forming genomic reassortants, the resulting vector preparations hypothetically contain a mix of homozygous and heterozygous vector particles. qRT-PCR was used to determine total and antigen-specific titers of ZVex-Multi vectors, defined as vector genome counts. Mice were immunized with ZVex-Multi vectors or monozygous vectors expressing multiple antigens from the same backbone to compare immunogenicity via intracellular cytokine staining. Two tumor models were used to evaluate therapeutic efficacy: 1) a B16 melanoma model, where tumor cells were inoculated in the flank and measured 2–3 times per week; and 2) a metastatic CT26 colon carcinoma model, where tumor cells were inoculated intravenously, and lung nodules were enumerated 17–19 days post-tumor inoculation.

Results

Titrations by qRT-PCR of multiple ZVex-Multi vector lots demonstrated that production yields of ZVex-Multi expressing up to four different tumor-associated antigens (e.g., NY-ESO-1, MAGE-A3) and two immuno-modulators (e.g., IL-12, anti-CTLA-4 or anti-PD-L1) were highly reproducible. Compared to mice immunized with vectors expressing multiple antigens from the same backbone, mice immunized with ZVex-Multi vectors consistently developed T cells against all targeted TAAs and exhibited improved tumor growth control and survival.

Conclusions

ZVex-Multi is a next generation DC-tropic vector platform designed to overcome limitations of single-genome vector platforms with respect to efficient co-expression of any combination of desired genes. Unlike other vector platforms, ZVex-Multi eliminates multiple cloning steps modifying the vector backbone, which can often result in unpredictable expression patterns of coded gene products. Its versatility and agility makes ZVex-Multi potentially the best-in-class vector platform for co-expression of multiple tumor antigens and immuno-modulators for enhanced cancer immunotherapy against a broad range of tumors.

P191 NK, T cells and IFN-gamma are required for the anti-tumor efficacy of combination-treatment with NKG2A and PD-1/PD-L1 checkpoint inhibitors in preclinical models

Caroline Denis1, Hormas Ghadially2, Thomas Arnoux1, Fabien Chanuc1, Nicolas Fuseri1, Robert W Wilkinson2, Nicolai Wagtmann1, Yannis Morel1, Pascale Andre1

1Innate Pharma, Marseille, Provence-Alpes-Cote d'Azur, France; 2MedImmune, Cambridge, England, UK
Correspondence: Pascale Andre (pascale.andre@innate-pharma.fr)

Background

Monalizumab (IPH2201) is a first-in-class humanized IgG4 targeting NKG2A, which is expressed as heterodimer with CD94 on the surface of NK, γδT and tumor infiltrating CD8+ T cells. This inhibitory receptor binds to HLA-E in humans and to Qa-1b in mice. HLA-E is frequently up-regulated on cancer cells, protecting from killing by NKG2A+ cells. Monalizumab blocks binding of CD94-NKG2A to HLA-E, reducing inhibitory signaling thereby enhancing NK and T cell responses. PD-1/PD-L1 inhibitors are successfully being used to treat patients with a wide variety of cancers. Combined blockade of NKG2A/HLA-E and PD-1/PD-L1 may be a promising strategy to better fight cancer by activating both the adaptive and innate immune systems.

Methods

To assess the effect of combined blockade of NKG2A/HLA-E and PD-1/PD-L1 in vivo, anti-mouse NKG2A and PD-1 antibodies were used in mice engrafted with A20 mouse B lymphoma cell line. For in vitro assays, anti-PD-L1 antibody durvalumab, and monalizumab were tested in human PBMC staphylococcal enterotoxin b assays.

Results

When cultured in vitro, the A20 cells express ligands for PD-1 but not for NKG2A. Exposure to IFN-γ in vitro, or subcutaneous injection into mice, induced expression of Qa-1b, resulting in a tumor model co-expressing PD-L1 and Qa-1b. Monotherapy with PD-1 or NKG2A blockers resulted in moderate anti-tumor efficacy while treatment with combination of NKG2A and PD-1 blockers resulted in a significantly higher anti-tumor immunity, and an increased rate of complete tumor regression. Depletion of either NK, or CD8+ T cells, or IFN-γ was enough to abrogate the efficacy of PD-1 and NKG2A blockade, indicating that both of these effector populations contribute to the efficacy of the combination treatment. To further explore this possibility and to assess the potential therapeutic relevance in humans, well-validated PBMC-based assays were used which showed that blocking both axes with a combination of durvalumab and monalizumab led to increased production of cytokines by both T and NK cells. Furthermore, the magnitude of the increase in cytokine secretion was dependent on the production of high levels of IFN-γ. Since IFN-γ is known to induce HLA-E this suggests that blockade of NKG2A could have a beneficial role in activation of immune cells through the combined blockade of PD-1/PD-L1.

Conclusions

Together, these data indicate that blocking NKG2A in conjunction with PD-1/PD-L1 checkpoint inhibitors provides increased anti-tumor efficacy mediated by IFN-γ and support the rationale for assessing this combination in clinical trials.

P192 Pharmacokinetics and immunogenicity of pembrolizumab when given in combination with ipilimumab: data from KEYNOTE-029

Michael B Atkins1, Matteo S Carlino2, Antoni Ribas3, John A Thompson4, Toni K Choueiri5, F Stephen Hodi5, Wen-Jen Hwu6, David F McDermott7, Victoria Atkinson8, Jonathan S Cebon9, Bernie Fitzharris10, Michael B Jameson11, Catriona McNeil12, Andrew G Hill13, Eric Mangin14, Malidi Ahamadi14, Marianne van Vugt15, Mariëlle van Zutphen15, Nageatte Ibrahim14, Georgina V Long16

1Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 2Westmead and Blacktown Hospitals, Melanoma Institute Australia, and the University of Sydney, Westmead, New South Wales, Australia; 3University of California, Los Angeles, CA, USA; 4University of Washington, Seattle, WA, USA; 5Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Harvard University, Boston, MA, USA; 6University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Beth Israel Deaconess Medical Center, Boston, MA, USA; 8Gallipoli Medical Research Foundation, Greenslopes Private Hospital, and the University of Queensland, Greenslopes, Queensland, Australia; 9Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia; 10Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand; 11Waikato Hospital Regional Cancer Centre, Hamilton, New Zealand; 12Royal Prince Alfred Hospital, Melanoma Institute Australia, the University of Sydney, and Chris O’Brien Lifehouse, Camperdown, New South Wales, Australia; 13Tasman Oncology Research, Southport Gold Coast, Queensland, Australia; 14Merck & Co., Inc., Kenilworth, NJ, USA; 15Quantitative Solutions, a Certara company, Oss, Netherlands; 16Melanoma Institute Australia, the University of Sydney, Mater Hospital, and Royal North Shore Hospital, Wollstonecraft, New South Wales, Australia