Background The orally available toll-like receptor 7 (TLR7) agonist prodrug RO7119929 is converted to active drug predominantly in the liver, where it is hypothesized to reprogram the local immune microenvironment. We aimed to explore the safety, pharmacokinetics (PK), and preliminary antitumor activity and obtain the proof-of-mechanism for RO7119929 in patients with liver cancer.Methods RO7119929 was investigated in mouse tumors and liver tissue from cynomolgus monkeys. In the first-in-human, open-label, dose-escalation and expansion study, patients with histologically confirmed advanced or metastatic primary liver cancers or solid tumors with predominant liver involvement received RO7119929 weekly in 3-week cycles either on a flat-dose (FD) or step-up dose (SUD) schedule.Results Preclinical results demonstrated antitumor activity and the proinflammatory proof-of-mechanism in mouse liver tumors and cynomolgus monkey liver tissue. The subsequent first-in-human study enrolled 27 patients in five FD dose-escalation cohorts, 18 patients in a FD dose-expansion cohort, and 9 patients in two SUD dose-escalation cohorts. The most common primary tumor type at study entry was hepatocellular carcinoma (HCC) (31%). PK data showed fast conversion of RO7119929 to the active TLR7 agonist. Treatment-related adverse events (TRAEs) were observed in 50 (91%) patients across all treated patients; the most commonly reported TRAE was cytokine release syndrome (CRS) in 48 (81%) patients. CRS was also identified as a dose-limiting safety risk and had a dose-dependent incidence and severity. Grade 3 CRS occurred in six (13%) patients receiving FD RO7119929, while no grade 3 CRS was reported in SUD patients at comparable target dose levels. TLR7-related transient, dose-dependent gene expression and cytokine induction was observed both with FD and SUD treatment and corresponded with treatment-induced local inflammation of the tumor microenvironment induced by reprogramming of the myeloid cells. Among 17 patients with HCC, one durable complete response was observed, and 10 (59%) patients had stable disease.Conclusions SUD appears to reduce the risk of CRS while maintaining mode-of-action-relevant pharmacodynamic effects. The clinical activity of RO7119929 as a single agent was limited, suggesting that combination therapy with a checkpoint inhibitor may be needed to leverage the proinflammatory potential of RO7119929 and further increase antitumor activity.Trial registration number NCT04338685.

Supplementary Fig. 6. Longitudinal analysis of on-treatment fold changes (log2) in peripheral regulatory T-cell subsets in tobemstomig-treated patients, stratified by cancer type.

Supplementary Fig. 5. Single-nuclei RNA sequencing analyses depicting gene-signature pharmacodynamic effects in NK cells from selected patients. The heatmap colors and significance annotations follow the same scheme as in Fig. 4d. Adj, adjusted; C, cycle; D, day.

Table S5. snRNA-Seq sample overview.

T-Cell Engagers (TCEs) have recently transformed the therapeutic landscape of hematological malignancies, including relapsed or refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). However, the variability in patient responses underscores the need for a deeper mechanistic understanding of the factors driving efficacy. Immune cell composition and T-cell functional states are emerging as critical determinants of immunotherapy outcomes. Recent advances in scRNA-seq technologies have enabled high-resolution characterization of T-cell states, revealing a spectrum from highly activated effectors to exhausted or dysfunctional subsets within the tumor microenvironment (TME). In this study, we conducted longitudinal scRNA-seq analyses and functional assessments of peripheral blood immune cells (PBMC) from glofitamab-treated R/R B-NHL patients, achieving complete metabolic responders (CMR) or progressive metabolic disease (PMD). Our findings reveal that the maintenance of naive-like (“fresher”) T-cell states (particularly the fresher cytotoxic T cells) at early timepoints is associated with clinical efficacy. In line with molecular data, T cells from responders exhibited enhanced functional activity compared to non-responders. Furthermore, the analysis of patient PBMCs and intra-tumor T cells from preclinical tumor models after consecutive glofitamab treatments revealed sustained functional activity, underscoring the long-term durability of T-cell responses. Combination of glofitamab with 4-1BB co-stimulation translated into increased proportions of intra-tumor T cells having a “fresher”, naive-like phenotype, ultimately leading to stronger anti-tumor efficacy. Taken together, our findings underscore the therapeutic relevance of “fresher” naive-like T-cell states and the potential of leveraging 4-1BB co-stimulation to overcome TCE resistance and improve clinical responses in aggressive lymphomas.

Table S8. Response assessment per RECIST version 1.1.

Abstract Purpose: The immunoglobulin G1–based bispecific antibody tobemstomig (RO7247669) simultaneously targets and blocks programmed cell death protein 1 and lymphocyte activation gene-3 expressed on activated T cells. Patients and Methods: This first-in-human, open-label, phase I clinical trial of tobemstomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with three tumor-specific cohorts, enrolling checkpoint inhibitor (CPI)–experienced patients with melanoma and non–small cell lung cancer (NSCLC) and CPI-naïve patients with esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), pharmacokinetics (PK), drug receptor occupancy, and preliminary antitumor activity. Results: Thirty-five (dose-escalation) and sixty-nine patients (expansion) were enrolled. Tobemstomig was well tolerated up to the highest tested dose of 2,100 mg once every 2 weeks. The MTD was not reached, and 2,100 mg once every 2 weeks was established as the RDE. Tobemstomig exhibited linear PK across the studied dose range. Partial responses were achieved by 2 of 4 (600 mg) and 4 of 13 (2,100 mg) patients during dose escalation, 6 of 41 patients with CPI-experienced melanoma [objective response rate (ORR): 15%; 95% confidence interval (CI), 6.6–26.9], and 1 of 8 patients with CPI-naïve ESCC (ORR: 12.5%; 90% CI, 0.6–47.1). Proof of mechanism was demonstrated in patients with CPI-experienced melanoma based on increases in the amounts of CD8+ T cells, expansion of stem-like CD8+ T cells, and the acquisition of cytotoxic effector functions, with limited changes in the regulatory T-cell compartment. Conclusions: Tobemstomig had a tolerable and manageable safety profile across various advanced solid tumor indications. The encouraging antitumor activity associated with pharmacodynamic activity and proof of mechanism in patients with CPI-experienced melanoma indicates the therapeutic potential of tobemstomig and supports further investigation in earlier disease treatment settings.

Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8+ and CD4+ TR. CD8+ TR cells were clonally expanded, and both CD8+ and CD4+ TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.

Abstract INTRODUCTION: Immune checkpoint inhibitors (ICI) in metastatic melanoma results in durable responses in ∼50% of patients. Our understanding of the tumour immune microenvironment (TME) features underpinning ICI response or resistance is currently incomplete. METHODS: To address this issue, we explored the TME of melanoma lymph node metastases (MLN mets) at a spatial (n = 32) and a single cell level (n=24). MLN mets were either from ICI-responder and ICI-resistant patients or untreated controls. We used multiplex IHC and our SPIAT algorithm to examine the spatial immune context of the TME, and also analyzed gene expression by RNAseq. Cells were also isolated from fresh tissue before or after ICI and analyzed by single cell RNAseq and TCRseq to derive high dimension data on T cells and their clonality, all other immune and melanoma cells. Finally, we performed cell-cell interactome and neighborhood analyses to reveal which cell and molecular interactions were associated with response. RESULTS: In patients who responded to ICI, both CD4+ and CD8+ tissue resident memory (TRM) T cell subset density were significantly increased within the tumor, and this correlated with closer distance to melanoma cells. (p<0.05). Single cell data revealed multiple clusters of immune cells (T, B, NK, Mø, DC) and melanoma cells. CD8+ T cell clustering revealed heterogeneous differentiation states. In ICI responders, we observed enrichment for TRM with an earlier transcriptional profile (TCF1+ Tpex.TRM and early TEM.TRM) and lower expression of the exhausted T cell (Texh) gene signature (p<0.05). Hyperexpanded CD8+ T cell clones were present in the TRM cell cluster and were enriched in the responder patients but not in those with resistant disease. CD4+ T cells showed both TRM and TFH clusters with shared expression of multiple genes, with CD4+ TRM also expressed a cytotoxicity gene module. Additionally, Mø and melanoma cells in resistant disease had significantly higher IFNg and IFN-I response gene expression levels compared to tumors from responders (p<0.05), suggesting that chronic activation of T cells in LN mets could lead to the observed Texh phenotype. Interactome analysis displayed putative interactions between CD4+ and CD8+ TRM via the CCL4-CCR5 axis in the ICI responders. This was confirmed by spatial analysis of neighborhood archetypes, which showed significantly increased cell-cell contact between both TRM subsets within the tumor of responders (p<0.05). Finally, conventional dendritic cells interact with both CD8+ and CD4+ TRM subsets in the tumor of responders, providing key signals for maintenance of the TRM pool within the tumor. CONCLUSIONS: MLN mets that respond to ICI are characterized by increased TRM comprising hyperexpanded TCR clones and complex TRM-containing neighborhood archetypes. Whilst these tumors show increased global inflammation, at a single cell level the resistant tumors have increased Texh and greater expression of IFN-regulated genes in melanoma cells and macrophages suggesting ineffective response to chronic antigen stimulation. Citation Format: Andrea Di Pietro, Lewis Au, Patrick Crock, Niko Thio, Angela Pizzolla, Marina Bacac, Ramona Schlenker, Aparna Rao, L Spain, David Gyorki, Shahneen Sandhu, Grant McArthur, Paul J Neeson. Tissue resident memory (TRM) T cells and dendritic cells form an in situ archetype for improved response to immune checkpoint therapy in metastatic melanoma [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 A006.

BACKGROUND:The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms. METHODS:We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed. FINDINGS:CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8+ T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function. CONCLUSIONS:Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response. FUNDING:This research was funded by Roche Pharma Research and Early Development.

Supplemental materials and methods

constructs, murine HCC model, spheroid and imaging, RCC tissue pathology

Background: It is hypothesized that TLR7 agonists reprogram myeloid cells in the TME, which may lead to activation of antitumor CD8 T effector cells and subsequently tumor cell death. The orally available TLR7 agonist prodrug RO7119929 is mainly converted into its active form in the liver. Here we report preclinical data informing the clinical proof of mechanism (PoM) strategy for RO7119929, as well as confirmatory clinical data from the first-in-human, Phase I study (NCT04338685). Methods: Prior to the Phase 1 study, bulk RNA sequencing of tumor and liver tissue was performed in a RO7119929 -treated HEP55.1c mouse model and RO7119929-treated cynomolgus monkeys. Single cell and single nucleus RNA-sequencing (snRNA-seq) was also performed in RO7119929 -treated human peripheral blood mononuclear cells (PBMCs). The Phase 1 study subsequently enrolled 55 pts with advanced primary liver cancers or other solid tumors with predominant liver involvement to receive weekly RO7119929. Paired pre- and post-treatment tumor liver biopsies were assessed. Pharmacodynamic (PD) monitoring of proximal and distal TLR7-related PD markers was performed using snRNA-seq, immunohistochemistry (IHC) and flow cytometry. Results: Preclinical mouse, cynomolgus monkey as well as human derived data showed dose-dependent, TLR7 mode of action-related, immune stimulatory reprogramming of PBMCs, the TME and liver tissue via myeloid cell activation. These findings were translated into a Phase I expansion cohort to demonstrate PoM using predefined PD gating criteria. By implementing snRNA-seq of paired liver biopsies from 11 pts, clinical PoM of RO7119929 could be demonstrated on a cellular and cytokine/chemokine level. Macrophages were the predominant immune infiltrate in liver tumor tissue and showed a relative increase in numbers and a trend towards an M1-immune stimulatory phenotype reprogramming on treatment. The local induction of proximal and distal cytokines and chemokines further confirmed a general shift towards a proinflammatory TME. In addition, peripheral CD8 T cell expansion was observed in most pts analyzed. An increase in CD8 tumor-infiltrating lymphocytes (TILs) occurred in 4/9 pts (all presented with stable disease) while most pts with no TIL increase had disease progression as best response. However, a general change towards a predominant CD8 inflamed immune phenotype was not detected. There was no trend for TLR7-induced increase in PD-L1 or MHC class I expression. Conclusions: Single-agent TLR7 agonist treatment of advanced primary or metastatic liver cancers induces local inflammation of the TME by reprogramming myeloid cells. Combination therapies may be needed to increase the relocation of antitumor CD8 T effector cells to the TME and unlock the full potential of the local immune stimulatory effect. Citation Format: Carles Fabregat-Franco, Changhoon Yoo, Bruno Sangro, Camilla Qvortrup, Hyung-Don Kim, Teresa Macarulla, Mariano Ponz-Sarvisé, Chia-Chi Lin, Do-Youn Oh, Thomas Yau, Juliana Bessa, Petra C. Schwalie, Steffen Dettling, Ramona Schlenker, Natascha Riede, Elia Hall, Felix Lichtenegger, Nicole Kratochwil, Thomas Pöschinger, Zhiwen Jiang, Tianyi Jiang, Christina Godfried Sie, Audrey Yeo Te-Ying, Christina Schiff, Sabine Hoves, Michael Cannarile. RO7119929, a TLR7 agonist prodrug, induces local inflammation of the tumor microenvironment (TME) by reprogramming myeloid cells in patients (pts) with advanced primary or metastatic liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2342.

Supplemental Video 3. In vitro visualization of the dynamics of CD20-TCB (white) during interaction between CD8+ T-cells (green) and tumor cells (blue). The video focuses on an example of CD20-TCB-mediated CD8+ T-cell cytotoxicity of tumor cells. T-cells surround the tumor cells and create stable synapses where CD20-TCB is localized (white). Tumor cells are killed upon certain time of T-cell/tumor cell interaction as evidenced by the formation of tumor blebs.

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1-4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6-10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

Expansion of antigen-specific effector CD8 T cells is central to the control of chronic viral infections and cancer. In particular, differentiation of antigen-experienced, PD-1+TCF-1+ stem -like CD8 T cells, termed here “resource T cells”, into effector cells is critical for the success of immunotherapies based on immune checkpoint PD-1 signaling blockade1-4. In the accompanying article, Hashimoto et al. show that in chronic infections, administration of the cytokine interleukin- 2 (IL-2) triggers an alternative differentiation path from resource T cells leading to the expansion of a distinct population of effector CD8 T cells, termed “better effectors”, which are similar to effector cells generated in an acute infection. IL-2 binding to the non-signaling component of its receptor, IL-2Rα-chain, also known as CD25, was essential to trigger this alternative differentiation path and to expand better effectors with distinct transcriptional and epigenetic profiles. However, as IL-2 binding to CD25 constitutively expressed on immunosuppressive regulatory T cells and on some endothelial cells contributes to unwanted systemic effects of IL-2 therapy that have hampered its broad clinical application, a new generation of engineered IL-2Rβγ-biased agonists with reduced/abolished CD25 binding is currently being developed5-9. Here we show that IL-2Rβγ-biased agonists devoid of CD25 binding are unable to preferentially expand better effectors in cancer models, and describe a novel antibody-cytokine fusion protein, PD1-IL2v, that overcomes the need for CD25 binding by using PD-1 binding in cis in order to generate this distinct effector cell population. PD1-IL2v comprises an engineered IL-2 variant devoid of CD25 binding, fused to a high affinity PD-1 blocking antibody. In cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell surface recovers the ability to differentiate resource CD8 T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models, while providing superior treatment efficacy. In contrast, PD-1/-L1 blocking antibodies alone, or their combination with clinically relevant doses of IL-2-based molecules with abolished CD25 binding and not targeted to PD-1, could not expand this unique subset of better effector T cells, and rather led to the accumulation of terminally-differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

Purpose: We examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective dose (BED), can independently and differentially affect the immunomodulatory capacity of radiation therapy (RT). Methods and Materials: AT3-OVA mammary and MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or with immune-modulating or-depleting agents. Tumor growth was monitored as a readout of therapeutic response. Flow cytometry and RNA sequencing of mouse tumors and analysis of transcriptomic data sets from irradiated human cancers were used to examine the immunomodulatory effects of the different radiation schedules. Results: In AT3-OVA tumors, radiation DPF rather than BED determined the ability of RT to evoke local antitumor CD8(+) T cell responses and synergize with anti-PD-1 therapy. Natural killer cell-mediated control of irradiated tumors was more sensitive to radiation BED. Radiation-induced regulatory T cell (Treg) responses, which were detected in both mouse and human tumors, were a major factor underlying the differential activation of adaptive immunity by radiation DPF and the activity of natural killer cells during the early phase of response to RT. Targeted inhibition of Treg responses within irradiated tumors rescued and enhanced local tumor control by RT and permitted the generation of abscopal and immunologic memory responses, irrespective of radiation schedule. MC38 tumors did not support the induction of an amplified Treg response to RT and were highly vulnerable to its immunoadjuvant effects. Conclusions: Local radiation-induced Treg responses are influenced by radiation schedule and tumor type and are a critical determinant of the immunoadjuvant potential of RT and its ability to synergize with T cell-targeted immunotherapy. (C) 2021 The Author(s). Published by Elsevier Inc.

Tumor-targeted 4-1BB agonists provide costimulation as combination partners for cancer immunotherapies in solid and hematological tumors.

High-dose IL-2 is approved for patients with metastatic melanoma and renal cell cancer, but is associated with significant toxicity. We have described tumor-targeted CEA-IL2v and FAP-IL2v immunocytokines that are based on an engineered IL2v moiety with abolished binding to IL-2Ra (CD25) to avoid undesired CD25-mediated toxicities and Treg expansion. Their antibodies bind with high affinity to either CEA or FAP, which are broadly expressed in various tumors, and mediate retention/accumulation in malignant lesions. In an effort to further maximize the potency of IL-2R activation of T cells (aka signal 3) without the side effects of wildtype IL-2, we have generated PD1-IL2v that binds to the checkpoint inhibitor PD-1 and delivers IL2v preferentially in cis to PD-1+ T cells substituting binding to CD25. This enables high affinity IL2R signaling selectively in recently primed antigen specific TILs and stem-cell like subsets. Binding/competition experiments demonstrated that PD1-IL2v is 50-fold more potent than FAP-IL2v in inducing p-STAT5 in PD-1 positive T cells, whereas it has equivalent potency on PD-1 negative T cells. Notably, although Tregs can express low constitutive levels of PD-1, PD1-IL2v shows preferential binding to Teff vs. Tregs. Furthermore, PD1-IL2v can overcome Treg suppression of Tconv effector cells to a greater extent than PD-1, FAP-IL2v or their combination. For use in syngeneic mouse models muPD1-IL2v was generated. In an orthotopic pancreatic Panc02-Luciferase model administration of muPD1-IL2v (1 mg/kg IV, qw) resulted in rapid and complete elimination of tumor cells (loss of luciferase signal) and in long term survival (> 140 days) in 7/7 treated animals with protection from tumor cell re-challenge, whereas only 1/7 animals in the muPD-1 + muFAP-IL2v combination group (10 mg/kg + 2.5 mg/kg IV, qw) and none of the animals treated with the respective monotherapies showed long term survival. IHC showed that the improved outcome with muPD1-IL2v was related to a strong intra-tumoral increase of CD3+ CD8+ T cells expressing PD-1 and GrzB. In an immuno-PD study with s.c. Panc02 tumors muPD1-IL2v strongly increased the number of IFNg+ TNFa+ multifunctional and cytotoxic GrzB+ PD-1+ T cells in the tumor accompanied with a 20-fold increase in CD8/CD4 ratio and a strong increase in the CD8+ TEM population resulting in subsequent tumor control or remission in 50% of the animals, respectively. In summary, our data demonstrate that preferential cis-targeting of IL2v to PD-1+ antigen specific T cells with PD1-IL2v results in a strong potentiation of T cell response and anti-tumor efficacy as compared to the combination of PD-1 checkpoint inhibition with FAP-IL2v. These preclinical data establish PD1-IL2v as a promising next generation IL-2 for cancer immunotherapy. Citation Format: Christian Klein, Laura Codarri-Deak, Valeria Nicolini, Stefan Seeber, Laura Lauener, Marine Richard, Esther Bommer, Maria Karagianni, Johannes Sam, Ramona Schlenker, Marisa Mariani, Petra Petra Schwalie, Sylvia Herter, Marina Bacac, Inja Waldhauer, Anne Freimoser-Grundschober, Volker Teichgraeber, Pablo Umana. A novel PD1-IL2v immunocytokine for preferential cis-activation of IL-2R signaling on PD-1 expressing T cell subsets strongly potentiates anti-tumor T cell activity of PD-1 checkpoint inhibition and IL-2R-beta-gamma agonism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1552.