Abstract B004: Identifying response factors to PD1-IL2v therapy
Authors: Manchala Amrita , Varypataki Eleni Maria , Karagianni Maria , Gralinska Elzbieta , Münz Christian , Klein Christian , Charo Jehad , Deak Laura Codarri 
Published: October 2024

Abstract
Immune checkpoint inhibitor agents have been widely explored as cancer immunotherapies, among which PD-1 blockade is most commonly used to treat several types of cancer. The outcome of such therapies is dependent on factors such as tumor immunogenicity and immune contexture, as well as intrinsic and adaptive resistance pathways. Among other modalities in immunotherapy, IL-2 was the first approved treatment for metastatic melanoma and RCC. Despite its long term efficacy, its use is limited by dose related toxicities, including capillary leak syndrome. The short half-life of IL-2 and the preferential targeting of Tregs, signifies that it has to be administered at high doses to reach CD8+ T cells, exacerbating the associated systemic toxicities. These considerable limitations have bolstered research efforts to identify safer ways to administer IL-2 without compromising its efficacy. PD1-IL2v was developed to deliver IL2Rβγ agonism to PD-1+ T cells, by combining a bivalent aPD-1 antibody and a mutated IL-2 moiety with abolished binding to IL-2Rα. The high affinity aPD-1 arm enables the preferential delivery of IL2v to PD-1+ T cells, including stem-like CD8+ T cells: a PD-1+TCF-1+ subset responsible for the clinical response to aPD-1 therapy and better disease prognosis. PD1-IL2v has shown superior efficacy over combinations of aPD-1 and stroma-targeted IL-2v in previously tested preclinical mouse tumor models, such as Panc02,B16-F10-OVA,MCA-205 and Rip-Tag5, however responses in MC38 and KPC-4662 were heterogeneous. One of the major hurdles with the usage of immunotherapies is determining which patients will respond to the therapy and to identify pre- or on- treatment biomarkers that associate with response or lack of response. In this study, we used YUMMER1.7(R)*, a mouse melanoma model bearing patient relevant driver mutations and a high tumor mutational burden similar to that found in human melanomas. PD1-IL2v treatment showed better tumor growth inhibition activity compared to aPD-1 and FAP-IL2v monotherapies. Ex-vivo re-stimulation of tumor infiltrating and tumor draining lymph node lymphocytes from PD1-IL2v treated mice showed activation of highly cytotoxic tumor-specific T cells.Although these cells were proven to be functional, based on their expression of TNFα and GrzB secretion, the tumors escaped control in treated mice around day 21. To assess potential combination partners able to overcome resistance to PD1-IL2v monotherapy, we tested PD1-IL2v with aPD-L1 and aCTLA-4. In addition, we are performing RNAseq to understand the transcriptional profile induced by the treatment and how this shapes response in the YUMMER1.7(R) model. Furthermore, to relate these findings to the clinical outcome of PD1-IL2v treated patients, we are analyzing ex-vivo PBMCs and TILs isolated from CPI naive and experienced solid tumor patients. Our ultimate aim is to identify a unique set of biomarkers and to translate this to clinical settings in order to aid in patient enrichment.*The YUMMER1.7 clone used in this project was generated in- house at Roche (R)
Citation Format: Amrita Manchala, Eleni Maria Varypataki, Maria Karagianni, Elzbieta Gralinska, Christian Münz, Christian Klein, Jehad Charo, Laura Codarri Deak. Identifying response factors to PD1-IL2v therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B004.