Abstract A68: Combining Deep IL-12 PrimedTM and Deep IL-15 PrimedTM T cells induces potent antigen-dependent in vitro cytotoxicity and in vivo antitumor activity
Authors: Geretti Elena , Sackton Katharine , Cao Pengpeng , Carey Shawn , Liang Xiaoyan , Nardozzi Jonathan , Gui Zishu , Worthylake Alicia , Hewes Becker , Maniar Tap , Fitzgerald Jonathan , Rakestraw Andy , Jones Douglas , Sauer Karsten , Andresen Thomas 
Published: March 2020

Background: Interleukin-15 (IL-15) and interleukin-12 (IL-12) play complementary roles as immunomodulators. IL-15 induces T-cell memory and supports survival, activation, and proliferation of CD8 T and NK cells. IL-12 promotes T-cell cytotoxicity and innate immune responses in the tumor microenvironment (TME). Both cytokines have been explored as cancer immunotherapies, but severe side effects have limited clinical success. Torque has developed the Deep-PrimedTM T-cell therapy technology to direct the stimulatory activity of these cytokines to the TME, to prime and boost the immune response of T-cell therapies with limited systemic exposure and toxicity. Multitargeted T cells (MTC) specific for multiple tumor antigens are generated from patient apheresis. Cytokines are tethered to MTCs to support MTC persistence and activity following adoptive transfer into patients, while limiting systemic cytokine exposure. This study evaluates the combination of Deep IL-15 PrimedTM and Deep IL-12 PrimedTM T cells to leverage their complementary biology for superior efficacy.

Methods: T cells reactive against MART-1 antigen were generated from healthy donors. Expansion and cytotoxicity of MART-1 T cells loaded with Deep IL-12, Deep IL-15, or both against cancer cells expressing MART-1 were assessed. Murine PMEL CD8 T cells reactive against the B16-F10 melanoma antigen gp100 were loaded with Deep IL-12, Deep IL-15, or both and evaluated for in vitro expansion, activation, and cytotoxicity against B16-F10 melanoma cells, as well as for antitumor activity in B16-F10 tumor-bearing mice.

Results: Loading with Deep IL-15 promoted MART-1 T cell proliferation and preserved antigen reactivity over time. Deep IL-12 enhanced IFNγ secretion and cytotoxicity, particularly at low effector:target ratios. Combination of MART-1 T cells loaded with Deep IL-12 and Deep IL-15 further enhanced T-cell expansion, IFNγ secretion, and cytotoxicity. Similarly, combination of murine PMEL T cells loaded with Deep IL-12 and Deep IL-15 resulted in persistent T-cell activation, improved memory, and enhanced cytotoxicity over individually loaded T cells. Coadministration of Deep IL-12 and Deep IL-15 loaded PMEL T cells to B16-F10 melanoma-bearing mice resulted in increased IFN-γ and IP-10 systemic cytokine release, indicative of enhanced immune response. The treatment was well tolerated with minimal and reversible body weight loss, and no changes in clinical chemistry. Importantly, the combination of Deep IL-12 and Deep IL-15 elicited superior antitumor activity.

Conclusions: Tethering DeepTM IL-12 and DeepTM IL-15 to T cells uniquely leverages their complementary functions as immunomodulators to maximize antitumor activity without notable toxicity in preclinical models. A phase I clinical trial of Deep IL-15 Primed MTCs (TRQ15-01) in solid cancers and lymphoma is enrolling (NCT03815682). Torque is initiating clinical evaluation of Deep IL-12 Primed MTCs (TRQ12-01), including in combination with TRQ15-01.

Citation Format: Elena Geretti, Katharine Sackton, Pengpeng Cao, Shawn Carey, Xiaoyan Liang, Jonathan Nardozzi, Zishu Gui, Alicia Worthylake, Becker Hewes, Tap Maniar, Jonathan Fitzgerald, Andy Rakestraw, Douglas Jones, Karsten Sauer, Thomas Andresen. Combining Deep IL-12 PrimedTM and Deep IL-15 PrimedTM T cells induces potent antigen-dependent in vitro cytotoxicity and in vivo antitumor activity [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A68.