INTRODUCTION:The systemic administration of cytokines is constrained by their pleiotropic activity, dose-dependent toxicities, and short serum half-life, limiting their therapeutic window in cancer treatment. To overcome these challenges, strategies that restrict cytokine signaling to defined immune cell subsets within the tumor microenvironment have been developed to enhance efficacy while minimizing off-target effects. Among these, antibody-cytokine fusion proteins represent a rational design platform that enables selective and localized cytokine delivery to specific immune populations. AREAS COVERED:This report outlines the design principles underlying tumor-associated antigen-targeted and cis-delivered IL-2- and IL-15-based immunocytokine platforms, with particular emphasis on the PD-1-directed cis-signaling strategy. Preclinical data on SOT201 are summarized, highlighting how its affinity optimized IL-15 mutein promote selective proliferation and enhanced effector function of PD-1+ CD8+ T cells. EXPERT OPINION:Cis-acting immunocytokines represent a promising class of advanced therapeutics that selectively direct cytokine payload to tumor infiltrating lymphocytes. This strategy has been shown to induce durable antitumor immunity and, in some cases, promote immune memory formation while limiting systemic toxicity. Ongoing clinical evaluation and rational combination approaches will ultimately define its therapeutic positioning in precision cancer immunotherapy.

Natural killer (NK) cells contribute to tumor immunosurveillance, yet their heterogeneity across cancer types remains incompletely understood. Transcriptomic, spatial, and functional assays reveal that non-small cell lung carcinoma (NSCLC) is enriched in NK cells that mediate clinically relevant effector functions, whereas high-grade serous ovarian carcinoma (HGSOC) contains dysfunctional NK cells that express co-inhibitory receptors including NKG2A. Analysis of HGSOC patient samples and syngeneic mouse models indicates a crosstalk between NK cells and CD8⁺ T cells critical for effective antitumor immunity. Depletion of either population leads to phenotypic impairment of the reciprocal one. Blocking NKG2A restores NK cell cytotoxicity and promotes CD8⁺ T cell responses, significantly improving the efficacy of PD-1 blockade in murine HGSOC models. Thus, NK cells and CD8⁺ T cells engage in a functional interplay of immunological relevance. Moreover, the NKG2A-HLA-E axis represents a clinically actionable immunological checkpoint in tumors with impaired NK cell functions.

Patients with gastric and pancreatic cancers, as well as other solid tumors including ovarian, lung, liver, and colon cancers, often lack effective therapeutic options. Claudin 18.2 (CLDN18.2) is a tumor-associated target that is predominantly expressed in gastric and pancreatic cancers but also found in several other tumor types. SOT102 is a novel antibody–drug conjugate directed against CLDN18.2, developed to provide a new therapeutic strategy for patients with CLDN18.2-positive tumors. SOT102, composed of a proprietary monoclonal antibody (mAb) conjugated to the cytotoxic payload PNU-159682, was evaluated for binding, internalization, and cytotoxic effects in vitro. The in vivo antitumor activity was assessed in patient-derived xenograft (PDX) and cell line-derived xenograft (CDX) mouse models, both as monotherapy and the latter in combination with anti-PD1 antibody therapy. SOT102 pharmacokinetics and tolerability were further investigated in cynomolgus monkeys following intravenous administration. SOT102 demonstrated selective binding to CLDN18.2, with no detectable cross-reactivity to CLDN18.1, and efficient internalization into CLDN18.2-expressing cell lines, resulting in potent cytotoxic effects against tumor organoids with half-maximal activity ranging from 0.2 nM to 19.4 nM. Antitumor activity against PDX-derived mouse models was observed at a minimum effective dose of 0.2 mg/kg, with enhanced efficacy when combined with anti-PD1 antibody treatment. SOT102 exposure in cynomolgus monkeys was dose-dependent at doses between 0.3 mg/kg and 1 mg/kg with a half-life of approximately 7 days. An acceptable tolerability profile was observed, and the therapeutic window was defined between the minimum effective dose in mice and the highest non-severe toxic dose (HNSTD) of 0.6 mg/kg in cynomolgus monkeys. SOT102 exhibited strong antitumor activity in preclinical models of CLDN18.2-positive cancers and demonstrated a favorable pharmacokinetic and safety profile in non-human primates. These data were used to support clinical evaluation of SOT102 as a potential treatment option for patients with CLDN18.2-expressing solid tumors.

NACT-mediated adjuvanticity positively impacts clinically relevant TLS maturation in metastatic HGSOC. A, Representative image of immunofluorescence of CD4, CD8, CD20, CD21, CD23, DC-LAMP, and GZMB staining (immunofluorescence panel 1). Scale bars, 10, 100 and 500 µm. B and C, Distribution of early TLS (eTLS; B) and mature TLS (mTLS; C) across pTME and mTME HGSOC tumor samples with/without NACT. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. D, Supervised hierarchical clustering of TLS-relevant gene signature (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) across pTME and mTME HGSOC tumor samples with/without NACT. E and F, Overall survival (OS) of 60 (E) and 40 chemo-naïve and treated patients with mHGSOC (F), respectively (study cohort 1 and 2) based on median stratification of total mTLS. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using log-rank test. Number of patients at risk and P values are reported. G, Number of mTLS across patients with CALRLo and CALRHi mHGSOC with/without NACT as determined by median stratification. Mean and SEM are shown. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. H and I, OS of 60 and 40 patients with chemo-naïve and treated mHGSOC (study cohorts 1 and 2), upon stratification based on median frequency of mTLS and expression of CALR. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using the log-rank test.

Colorectal cancer is the third most prevalent type of cancer, with an incidence of nearly 2 million new cases annually, and ranks as the second leading cause of cancer mortality worldwide. CDH17 is a single-pass transmembrane glycoprotein involved in calcium-dependent cell-cell adhesion and epithelial homeostasis regulation. In normal physiology, CDH17 is predominantly localized on the lateral surfaces of intestinal and pancreatic ductal epithelial cells​. However, it is frequently overexpressed and aberrantly localized in gastrointestinal tumors including colorectal, gastric, pancreatic and gastroesophageal carcinomas. We have developed SOT109, a proprietary CDH17 targeting exatecan-based antibody-drug conjugate (ADC) and evaluated its preclinical safety and efficacy. Immunohistochemical staining of patient tumor and healthy tissue microarrays confirmed CDH17 expression in normal tissues including the colon, stomach and small intestine, with pronounced expression in colorectal, gastric, and gastroesophageal junction tumors, consistent with previously published literature. SOT109 candidates were generated from a fully human CDH17 monoclonal antibody conjugated via a hydrophobic linker to exatecan, a cytotoxic topoisomerase I inhibitor payload. Candidates were selected by rigorous screening for optimal binding epitopes and affinity, together with binding, internalization, and cytotoxicity in vitro. SOT109 candidates demonstrated specific binding to CDH17 and selective internalization and killing of target-positive cancer cells. Lead candidates underwent evaluation in several preclinical in vivo mouse tumor models, including cell-derived and patient-derived xenografts. Treatment with SOT109 resulted in profound and sustained tumor regressions. The doses tested in these studies were well tolerated in mice, with no dose-limiting toxicities observed. Subsequent studies in non-human primates revealed a favorable pharmacokinetic and safety profile. SOT109 targets the overexpressed tumor antigen CDH17 and exhibits potent anti-tumor efficacy coupled with a clean safety profile in preclinical models of colorectal carcinoma. These data suggest that SOT109 holds significant potential as a therapeutic candidate for patients with gastrointestinal malignancies and supports the further clinical development of SOT109. Nataliia Kalynovska, Diana Hudecz, Matous Hrdinka, Ilona Prochazkova, Eliska Kohelova, Lenka Palova Jelinkova, Filip Jaburek, Tomas Zimmermann, Lukas Fojtik, Irena Adkins, Sarka Stehlikova, Amy Jensen-Smith, Radek Spisek, Martin Steegmaier. Preclinical safety and efficacy of SOT109, an antibody-drug conjugate targeting cadherin 17 (CDH17) for the treatment of colorectal and other gastrointestinal tract tumors [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 5469.

Immunomodulation by NACT in metastatic HGSOC. A, Representative images of CALR immunostaining in CALRLo and CALRHi patients. Scale bars, 10 and 100 µm. B, CALR expression levels determined by immunostaining and (C) ER stress signature level [expression level of DNA damage inducible transcript 3 (DDIT3, best known as CHOP), heat shock protein family A (Hsp70) member 5 (HSPA5, best known as BIP), and heat shock protein 90 beta family member 1 (HSP90B1)] as determined by RNA-seq in pTME and mTME HGSOC with/without NACT. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. D, Supervised hierarchical clustering of gene signatures related to immune populations (orange), immune functions (blue) and immune phenotype (purple) as determined by RNA-seq data from pTME and mTME HGSOC tumor samples with/without NACT. IS, immunosuppression; mDCs, myeloid dendritic cells; NK cells, natural killer cells; TLS, tertiary lymphoid structures. E, Gene expression signature associated with CD8+ T cells, B cells, cytotoxicity, mDCs, TLS, and immunosuppression as determined on RNA-seq data from pTME and mTME HGSOC with/without NACT. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. F, Representative image of CD20/DC-LAMP double immunostaining. Scale bars, 500 and 100 µm. G, Density of CD8+ T cells, CD20+ B cells, and DC-LAMP+ cells as determined by immunostaining in pTME and mTME HGSOC samples with/without NACT. Mean and SEM are shown. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. ns, not significant.

AbstractPurpose: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. Experimental Design: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. Results: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. Conclusions: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10

Univariate Cox proportional hazard analyses.

NACT-mediated adjuvanticity positively impacts the density of follicular T cells (TFH) and in situ activation of intratumoral B cells in mHGSOC. A–C, Representative image (A) and box plots showing the density of CD4+ cells (B) and CXCR5+PD1+FoxP3−CD4+ TFH cells (C) in the pTME and mTME of chemo-naïve and treated HGSOC (study cohort 1 and 2). Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by the Mann–Whitney test. P values are indicated. D and E, Dot plot (D) and box plot (E) showing expression profile of gene signatures of B-cell subtypes, e.g., plasma cells (PC), germinal center (GC), and memory B cells within pTME and mTME HGSOC tumor samples with/without NACT. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. F and G, Representative image (F) and density of CD68+CD163+ TAMs in pTME and mTME of chemo naïve and treated HGSOC (G). Mean and SEM are shown. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated.

Supplemental material, figures and tables

BACKGROUND:SOT201 and its murine surrogate mSOT201 are novel cis-acting immunocytokines consisting of a humanized/murinized/, Fc-silenced anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) fused to an attenuated human interleukin (IL)-15 and the IL-15Rα sushi+ domain. Murine mPD1-IL2v is a conjugate of a murinized, Fc silenced anti-PD-1 mAb bearing human IL-2 with abolished IL-2Rα binding. These immunocytokines spatiotemporally reinvigorate PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs) via cis-activation and concomitantly activate the innate immunity via IL-2/15Rβγ signaling. METHODS:Human peripheral blood mononuclear cell and cell lines were used to evaluate cis/trans activity of SOT201. Anti-PD-1 mAb responsive (MC38, CT26) and resistant (B16F10, CT26 STK11 KO) mouse tumor models were used to determine the anticancer efficacy, and the underlying immune cell activity was analyzed via single-cell RNA sequencing and flow cytometry. The expansion of tumor antigen-specific CD8+ T cells by mSOT201 or mPD1-IL2v and memory CD8+ T-cell generation in vivo was determined by flow cytometry. RESULTS:SOT201 delivers attenuated IL-15 to PD-1+ T cells via cis-presentation, reinvigorates exhausted human T cells and induces higher interferon-γ production than pembrolizumab in vitro. mSOT201 administered as a single dose exhibits strong antitumor efficacy with several complete responses in all tested mouse tumor models. While mPD1-IL2v activates CD8+ T cells with a 50-fold higher potency than mSOT201 in vitro, mSOT201 more effectively reactivates effector exhausted CD8+ T cells (Tex), which demonstrate higher cytotoxicity, lower exhaustion and lower immune checkpoint transcriptional signatures in comparison to mPD1-IL2v in MC38 tumors in vivo. This can be correlated with a higher rate of complete responses in the MC38 tumor model following mSOT201 treatment when compared with mPD1-IL2v. mSOT201 increased the relative number of tumor antigen-specific CD8+ T cells, and unlike mPD1-IL2v stimulated greater expansion of adoptively transferred ovalbumin-primed CD8+ T cells simultaneously limiting the peripheral CD8+ T-cell sink, leading to the development of memory CD8+ T cells in vivo. CONCLUSIONS:SOT201 represents a promising therapeutic candidate that preferentially targets PD-1+ TILs, delivering balanced cytokine activity for reviving CD8+ Tex cells in tumors. SOT201 is currently being evaluated in the Phase I clinical study VICTORIA-01 (NCT06163391) in patients with advanced metastatic cancer.

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8+ T cells, thereby promoting an innate and adaptive anti-tumor inflammatory microenvironment in mouse tumor models either in monotherapy or combined with an anti-programmed cell death protein 1 (PD-1) antibody. In cynomolgus monkeys, a clinical schedule was identified, which translated into the design of a phase 1/1b clinical trial, AURELIO-03 (NCT04234113). In 51 patients with advanced/metastatic solid tumors, nanril increased the proportions of CD8+ T cells and NK cells in peripheral blood and tumors. It had a favorable safety profile when administered subcutaneously on days 1, 2, 8, and 9 of each 21-day cycle as monotherapy (0.25-15 μg/kg) or combined (1.5-12 μg/kg) with the anti-PD-1 pembrolizumab (200 mg). The most frequent treatment-emergent adverse events were pyrexia, injection site reactions, and chills. Furthermore, early clinical efficacy was observed, including in immune checkpoint blockade-resistant/refractory patients.

NACT positively increases the ICI-sensitive TCF1+PD1+CD8+ T-cell phenotype within metastatic HGSOC. A, Representative image of immunofluorescence of CD68, CD8, PD-L1, FoxP3, TCF1, CD57, PanCK, PD1, CD4, CD20, GZMB, and TIM-3 staining (immunofluorescence panel 2). Scale bars, 2 μm, 10 µm, and 100 µm. B, Violin plot showing the density of CD8+ and PD1+CD8+ within tumor core and tumor stroma of pTME and mTME of chemo-naïve and treated HGSOC. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. C and D, Representative image (C) and box plot showing the density of TCF1+PD1+CD8+ T cells and TIM-3+PD1+CD8+ and spatial distribution of TCF1+PD1+CD8+ T cells within tumor core and stroma in pTME and mTME of chemo-naïve and treated HGSOC (D). Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. E, Supervised hierarchical clustering of gene signatures associated with different stages of T-cell differentiation: T-cell stemness (orange), T-cell effector function (blue), T-cell proliferation (green), T-cell phenotype (red) as determined by RNAseq in mTME of chemo-naïve and treated HGSOC. For further details, see Supplementary Fig. S9. F and G, Representative image of digital pathology spatial distribution and violin plot showing the number of cell contacts between PanCK+ malignant cells and TCF1+PD1+CD8+ T cells and TIM-3+PD1+CD8+ within 0 to 30 µm in pTME and mTME of chemo-naïve and treated HGSOC.

Background High densities of tertiary lymphoid structures (TLSs) are associated with improved clinical outcomes in various malignancies, including human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). However, the role of TLSs in shaping antitumor immunity in HPV-induced cervical cancer (CESC) remains unclear. Therefore, we analyzed the density, composition, and prognostic impact of TLSs in patients with CESC as well as patients with HNSCC.Methods Multiplex immunofluorescence, immunohistochemistry, and spatial transcriptomics were used to analyze TLS density and composition in HNSCC and CESC tissue sections with respect to patient prognosis. The spatial approach was supplemented by flow cytometry-based analysis of the polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype in freshly resected primary tumor tissues.Results Although both indications were associated with HPV infection, we confirmed a positive correlation between TLS density and improved overall survival only in patients with HNSCC. The TLS composition differed markedly between HNSCC and CESC samples, with a shift toward high regulatory T cell (Treg) and PMN-MDSC abundance in CESC samples. The highest Treg and PMN-MDSC levels were observed in patients with CESC who died of the disease. CESC-infiltrating PMN-MDSCs showed high arginase 1 expression, which correlated with diminished T-cell receptor (TCR)ζ chain expression in CESC-infiltrating T cells. Additionally, the high number of PMN-MDSCs in TLSs was associated with the absence of HPV-specific T cells in CESC.Conclusions Unlike in HNSCC, the composition of TLSs, rather than their quantity, was associated with the overall survival of patients with CESC. High numbers of Tregs and PMN-MDSCs infiltrating immature TLSs prevail in patients with CESC who succumbed to the disease and seem to affect tumor-specific immune responses.

The clinical relevance of combined chemotherapy and immunotherapy in mouse models of TMBLo and TMBHi ovarian cancer. A and B, Bar plots showing single-nucleotide variants positions (SNVs) (A) and the somatic mutations prevalence (mutations per megabase) (B) in ID8 (n = 3) and Brca1−/−Trp53−/−/Myc/Hras SO1 (n = 3) C57BL/6 syngeneic mouse ovarian cancer cell lines. Mean and SEM are shown. Statistical significance was calculated by multiple t test. P values are indicated. C, Experimental design for the analysis of TLS aggregates development and efficacy of combined chemotherapy and aPD1 and/or aTIM-3 therapy in TMBLo ID8 and TMBHi SO1 experimental syngeneic mouse models. D and E, Representative immunostaining for CD4, CD8, CD20, and CD21 (D) and a box plot showing density of TLS aggregates within chemo-naïve (n = 5) and treated TMBHi SO1 (n = 9) ovarian tumors (E). Scale bars, 100 µm and 2.5 mm. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. F–H, Representative dot plot (F) and flow cytometry analyses for percentages of CD62L+CD44+ central memory (CM) and CD62L−CD44− terminally differentiated CD8+ T cells (TEMRA) (G) and TCF1+PD1+CD8+ and TIM-3+PD1+CD8+ T cells (H) in tumor samples of the TMBHi SO1 experimental model in the presence or absence of carboplatin and taxane chemotherapy (NACT). Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. I and J, Overall survival (OS) of TMBHi SO1 experimental model (I) and flow cytometry analyses for percentage of TCF1+PD1+CD8+ T cells after NACT, aPD1, aTIM-3 and combined therapy (J). Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using log-rank test. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. K and L, Representative immunostaining for CD4, CD8, CD20, and CD21 (K) and a box plot showing density of TLS aggregates within chemo-naïve (n = 8) and treated TMBLo ID8 (n = 8) (L) ovarian tumors. Scale bars, 100 µm and 2.5 mm. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. M, Flow cytometry analyses for TCF1+PD1+CD8+ and TIM-3+PD1+CD8+ T cells in tumor samples of the TMBLo ID8 experimental model in the presence or absence of carboplatin and taxane chemotherapy (NACT). Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by two-sided Mann–Whitney test. P values are indicated. N, Overall survival (OS) of TMBLo ID8 experimental model after NACT, anti-PD1, and combined therapy. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using log-rank test. P values are indicated. (Panel C created with BioRender.com.)

NACT-mediated progenitor TCF1+PD1+CD8+ T-cell phenotype associates with effector cytotoxic functions within metastatic HGSOC. A–C, Representative dot plot (A) and box plot (B) showing percentage of TIM-3+PD1+CD8+ T cells and GZMB+CD8+ T cells within native pTME and mTME of chemo-naïve and treated HGSOC as determined by flow cytometry. Box plots: lower quartile, median, upper quartile; whiskers, minimum, maximum. Statistical significance was calculated by the Mann–Whitney test. P values are indicated. C, Marker heatmap dot plots obtained after t-SNE and showing the relative expression of the indicated marker in the different phenotypic clusters within mTME of chemo-naïve and treated HGSOS as determined by flow cytometry. D, Design of experimental and sequencing workflow in 11 patients with HGSOC before and after NACT. scRNAseq was performed on dissociated solid tumor specimens using 10× Genomics Chromium platform. E and F, Uniform manifold approximation and projection (UMAP) plot of all cells (n = 51,476) passing the quality control, colored by type of therapy (E) and cell type (F). G and H, TILs projections (G) and predicted subtype frequencies (H) in biopsies from patients with chemo-naïve and treated HGSOC. CM, central memory; EM, effector memory; MAIT, mucosal-associated invariant T cells; PTEX, progenitor exhausted T cells; TEMRA, terminally exhausted T cells; TEX, exhausted T cells. I and J, Radar plot showing percentage of CD8+ T cells expressing respective T-cell marker (KLRB1, TCF7, CCR7, IL7R, LMNA, FGFBP2, XCL1, CD200, CRTAM, TOX, PDCD1, HAVCR2, and GNLY; I) and UMAP showing expression of PDCD1, HAVCR2 and TCF7 in CD4+ and CD8+ T-cell clusters in chemo-naïve and treated HGSOC samples (study cohort 5; J), as determined by scRNA-seq. (Panel D created with BioRender.com.)

The leucine-rich repeat containing protein 15 (LRRC15) is crucial for cell-cell and cell-extracellular matrix interactions. Normal tissue expression is minimal and primarily restricted to the placenta, hair follicles in the skin, and is also increased in activated fibroblasts during wound healing. In cancer, LRRC15 is overexpressed in mesenchymal malignancies including sarcomas and glioblastoma, and in cancer-associated fibroblasts (CAFs) of various epithelial tumors including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or pancreatic ductal adenocarcinoma (PDAC). Thus, LRRC15 is a promising therapeutic target, particularly for disrupting tumor-stroma interactions that support tumor growth and hinder chemotherapy effectiveness. SOT106 is a novel antibody-drug conjugate (ADC) targeting LRRC15, comprised of a proprietary humanized monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a beta-glucuronidase (GUSB) cleavable linker for tumor specific payload release. In in vitro studies, SOT106 showed strong antigen-specific binding, efficient internalization, and cytotoxicity in the low nanomolar range. Strong and durable dose-dependent tumor growth reduction was observed in several disease-relevant mouse models, with complete responses achieved following administration of a well-tolerated and clinically relevant dose of 1 mg/kg. Importantly, SOT106 achieved efficacy at a lower dose and with less frequent administration compared to the clinical benchmark. In an exploratory study in cynomolgus monkeys, SOT106 demonstrated favorable pharmacokinetic properties with a half-life of 4.5 to 6 days without premature payload release, a preliminary non-severely toxic dose (HNSTD) of approx. 10 mg/kg, and a broad therapeutic index of 40 based on allometric scaling. Further, significantly increased plasma stability was observed over the course of 14 days. Dose-limiting toxicities were consistent with the known MMAE-mediated effects. In parallel, we have also developed a highly specific proprietary diagnostic antibody to be used for prospective patient selection in Phase I/Phase II clinical trial. In summary, SOT106 is a highly effective and well-tolerated LRRC15 targeted ADC that holds promise for the clinical treatment of patients with sarcomas and other LRRC15-positive tumors. Michaela Fojtu, Iva Valentová, Eliška Kohelová, Tomáš Zimmermann, Šárka Stehlíková, Irena Adkins, Nataliia Kalynovska, Lenka Palová Jelínková, Filip Jabůrek, Ann Ranger, Ulrich Moebius, Martin Steegmaier, Amy Jensen-Smith, Radek Špíšek. SOT106, a novel best-in-class antibody-drug conjugate targeting LRRC15, to treat sarcomas and other advanced solid cancers [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 1164.

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.