We are pleased to present highlights of the latest advances in immunotherapy emerging from the ESMO Immuno-Oncology Congress 2025, Dec. 10–11, 2025.
Clinical and translational studies of neoadjuvant pembroluzmab and lenvatinib in patients with resectable early-stage lung cancer
LBA1. Neoadjuvant induction with pembrolizumab (Pembro) plus lenvatinib (Len) in resectable early-stage NSCLC impacts the tumor microenvironment (TME): Clinical results including multi-omic deconvolution of the TME from the INNWOP01 study
Andreas Pircher (Innsbruck Medical University, Innsbruck, Austria) presented results from the INNWOP01 study a single-center phase 2 study evaluating the efficacy of neoadjuvant pembrolizumab plus the VEGF receptor (VEGFR) tyrosine kinase inhibitor lenvatinib in patients with resectable non-small cell lung cancer (NSCLC). 31 patients received two induction cycles of pembrolizumab plus lenvatinib followed by surgery and adjuvant pembrolizumab (n=20) or adjuvant chemotherapy (n=5). 10 patients (32.1%) experienced a major pathologic response (MPR; viable tumor cells <= 10%), one patient (3.2%) achieved pathologic complete response (no viable tumor cells), and 22 (71.0%) experienced a partial pathologic response (viable tumor cells <= 50%). MPRs were concordant with high PD-L1 expression and with metabolic response, as indicated by FDG-PET. 97.0% of patients experienced an adverse event (AE); most AEs were grade 1 or 2, and all were manageable. No unexpected safety signals were observed, and all surgeries occurred as scheduled. Tumor samples obtained before and after neoadjuvant treatment underwent multi-omic analysis to characterize the tumor microenvironment (TME). Samples from patients with an MPR exhibited tumor microenvironment (TME) remodeling, indicated by a significant expansion of exhausted CD8 T cells and effector memory CD8 T cells and formation of tertiary lymphoid structures, compared to samples from patients who did not have an MPR. Tumors from patients without an MPR exhibited enriched levels of tumor-associated neutrophils with pro-angiogenic phenotypes. This first-in-class study indicates that neoadjuvant therapy with pembrolizumab and lenvatinib is safe and feasible and is associated with clinical responses in patients with early-stage NSCLC. Results from the translational studies suggest that MPRs are associated with patterns of immune remodeling of the TME, and that expansion of neutrophils in tumors that did not respond to combination therapy may underly a novel mechanism of resistance to PD-1/VEGFR blockade.
Exploring the dynamics of acquired resistance to adoptive cellular therapy with tumor-infiltrating lymphocytes
LBA4. Genomic and functional drivers of acquired resistance to TIL-ACT
Mario Presti (Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark) reported a retrospective study to understand the dyamics of acquired resistance (AR) to adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT). Although TIL-ACT can induce a response in most patients with immune checkpoint inhibitor (ICI)-resistant melanoma, approximately one-third of initial responders develop AR. The TIL-Acquired Resistance Cohort included samples from 20 patients with ICI-resistant melanoma, represent four different trials of TIL-ACT, who experienced an objective response and progression on TIL-ACT. Tumor samples at baseline and during tumor progression underwent functional and multi-omic analyses. Of the 15 tumors that underwent genomic analysis, almost all had genomic alterations associated with ICI resistance, which was to be expected since 14 of 15 patients had ICI-resistant melanoma. 8 of 15 patients had de novo genomic alterations that were known to drive resistance, either through genomic immune escape (n=3) or through proliferation pathways (n=5). Transcriptomic analyses of tumors during progression showed downregulation of pathways associated with an immune response, including interferon signaling and antigen processing, which was confirmed with paired samples. Paired samples that exhibited an inflamed tumor microenvironment (TME) at baseline did not exhibit a similar TME at progression, also suggesting the association of immunosuppression with AR. Functional analyses indicated that while progression tumors exhibited lower CD8 TIL reactivity, these tumors still contained tumor-reactive TILs. Taken together, these results suggest that like AR to ICIs, AR to TIL-ACT is a complex phenotype that often involves genomic alterations to drive a hyperproliferative state of tumor cells coupled with neural-crest-like phenotype or immune evasion. This finding is likely due to the selection of tumors that developed resistance after multiple lines of immunotherapy. Tumor reactive TILs remained present in tumors during progression, suggesting anti-tumor immunity is occurring in resistant tumors, albeit less effectively, and could potentially be rescued.
Identification of transcriptional regulator Med16 as a putative regulator of anti-tumor immunity and potential immunotherapy target
327MO. In vivo CRISPR/Cas9 genetic screens identify novel immunotherapy target
Dimitrios A. Garyfallos (University College London Cancer Institute, London, United Kingdom) presented results from a screen to identify genes that regulate anti-tumor immunity, ultimately discovering new immunotherapy targets. Cas9-expressing colon cancer MC38 cells were transduced with a lentiviral guide RNA library for genome-wide screening, and edited cells were screened in vitro and introduced into immunocompetent mice. Candidate genes that, when deleted, were depleted in tumors in vivo in immunocompetent mice were subcloned in a validation gRNA library and re-screened to identify genes that, when deleted, were not represented in tumors from immunocompetent mice but were highly represented in tumors from immunocompromised mice. Med16, an RNA polymerase II transcriptional regulator, was identified to respond to stimuli. Previous studies suggest Med16 may have a repressive function in yeast, and a previously publication identified Med-16 as a potential immunotherapy target. Med-16 was knocked out (Med16-KO) in MC38 colon cancer cells and in KPB6 lung cancer cells, and both Med16-KO cell lines were implanted in immunocompromised and immunocompetent mice. Tumor rejection of the Med16-KO lines occurred in the immunocompetent mice but not in the immunocompromised mice, and implantation with Med16-KO cancer cell lines was associated with significantly improved survival in immunocompetent mice compared to immunocompetent mice implanted with cell lines expressing Med16. Med-16 KO tumors contained expanded clones of effector memory CD8 T cells, and survival of mice implanted with Med16-KO tumors was dependent on CD8 T cells. Med16-KO led to a global increase in transcription within the cell, including genes involved in type I and type II interferon signaling. Blockade of Type I and Type II interferon signaling in mice with Med16-KO tumors led to survival phenotypes similar to mice with wild type tumors, suggesting the anti-tumor immune response against Med16-KO tumors was dependent on interferon signaling. Co-culturing human PBMCs with Med16-KO human cell lines, resulted in increased T cell activation and cytotoxicity, compared co-cutures with wild type Med16 cell lines. Med16-KO was associated with increased alternative splicing events (i.e. more predicted presentable novel splice transcripts) and with reactivation of endogenous retroviral elements, providing potential mechanisms of action underlying the immunogenicity of Med16-KO tumor cells.
Macrophage expression of chitinase-1 as a biomarker of response in patients receiving neoadjuvant immune checkpoint blockade and chemotherapy for triple negative breast cancer
328MO. Residual tumour immune microenvironment shapes relapse risk in early TNBC following immunotherapy
Kevin Mulder (The Francis Crick Institute, London, United Kingdom) presented a retrospective study to identify immune determinants and predictive biomarkers of response to immune checkpoint inhibitors plus chemotherapy for triple negative breast cancer (TNBC). Tumor samples from 48 patients who received neoadjuvant pembrolizumab and chemotherapy were analyzed and scored for residual cancer burden (RCB). Low RCB corresponded to low chances of relapse, and high RCB corresponded to high chance of relapse. Samples were then processed for spatial transcriptomic studies. Immune remodeling of the tumor microenvironment correlated well with RCB. Tumors from patients with lower RCB correlated with increased levels of lipid-laden macrophages that expressed and secreted the unique biomarker chitinase-1 (CHIT1), and this was observed at transcriptional/RNA and translational/protein levels. This accumulation was not observed in patients with higher RCB. To investigate the feasibility of CHIT1 as a potential biomarker of response, blood samples from patients at baseline and 6 weeks on-treatment were analzyed. In the on-treatment samples, levels of CHIT1 protein in the blood were significantly higher in patients with low RCB scores (RCB 0 and I) compared to patients with high RCB scores (II), suggesting CHIT1 could be used as a biomarker to monitor response. To investigate the potential of CHIT1 as a predictive biomarker of response, baseline levels of CHIT1 were also analyzed. Similar results were observed, with higher baselline levels of CHIT1 in patients with low RCB scores (0-I) compared to patients with higher RCT scores (II). Increased levels of CHIT1 in blood at baseline were also associated with improved progression-free survival. Validation of these findings is ongoing, and the investigators are open to incorporating additional clinical trial cohorts in validation studies.
B cell dynamics and antibody production in patients receiving neoadjuvant pembrolizuamb for mismatch repair defective endometrial cancer
329MO. Neoadjuvant immune checkpoint inhibition skews the B cell response in mismatch repair deficient endometrial cancer
Hans Nijman (University Medical Center in Groningen, Groningen, Netherlands) reported a translational study of B cell activity from a Phase 1 study of neoadjuvant pembrolizumab for mismatch repair deficient (MMRd) endometrial cancer. Spatial transcriptomic analyses identified tertiary lymphoid structures (TLS) at the edges of tumors, and the presence of highly organized mature TLS corresponded to response. IgG- and IgA-positive cells were identified in tumor tissue of multiple subtypes of endometrial cancer, including MMRd subtypes. High levels of IgG and IgA were associated with better prognosis. IgA has significantly higher somatic hypermutation than IgG. Germinal center B cells in TLS of dMMR tumors were surrounded by T cells. In patients who received neoadjuvant pembrolizumab, shifts in local antibody isotypes were observed, with numerous IgG responses but minimal IgA responses. While these results indicate that B cells contribute to the immune landscape in MMRd endometrial cancer and that B cells are modulated by neoadjuvant immune checkpoint inhibitors, they also generate new questions surrounding antibody production and neoadjuvant immune checkpoint inhibitors. Additional studies focusing on B cell dynamics and antibody production during immunotherapy are ongoing, and early results from the Phase 1-2 PAM-II trial investigating the efficacy of nine cycles of neoadjuvant pembrolizumab form MMRd endometrial cancer will be reported soon.
iSCIB1+, an off-the-shelf DNA plasmid vaccine, in combination with immune checkpoint blockade, for first-line treatment of unresectable melanoma
LBA3. SCOPE, phase II clinical trial with off-the-shelf DNA plasmid vaccine in first line advanced melanoma combined with check point blockade
Heather M. Shaw (Mount Vernon Cancer Centre and University College London Hospital, London, United Kingdom) presented updated safety and efficacy data from SCOPE, a phase 2 clinical trial of an off-the-shelf DNA plasmid vaccine in combination with immune checkpoint inhibitors for first-line treatment of advanced melanoma. The vaccines SCIB1 and iSCIB1+, developed with the ImmunoBody platform, are administered by intramuscular needle-free injection delivered through the skin under pressure. SCIB1 and iSCIB1+ encode modified antibodies engineered to express CD8 and CD4 epitopes from melanoma proteins TRP-2 and gp100 and facilitate the anti-tumor immune response by targeting activated antigen presenting cells and facilitating the MHC class I-mediated T cell anti-tumor response. iSCIB1+, a next-generation version of SCIB1, has been modified to encode additional epitopes applicable to more HLA MHC-class I haplotypes and for increased avidity. Patients with previously untreated unresectable melanoma received SCIB1 or iSCIB1+ in combination with standard of care checkpoint inhibitors ipilimumab and nivolumab followed by nivolumab. At a mean follow-up of 10.5 months among 80 evaluated patients, the 26-month progression-free survival (PFS) was 60%, the disease control rate was 81%, the overall response rate was 60%, and 12 patients experienced a complete response. Among patients receiving iSCIB1+ representing a broader range of HLA haplotypes (n=39), 16-month PFS was 74%. Overall survival (OS) data were only available in the cohort of HLA-restricted patients receiving SCIB-1 (n=41), and 26-month OS in this population was 77%. The next-generation iSCIB1+ was associated with a 12% improvement in PFS compared to SCIB1. SCIB1 and iSCIB1+ in combination with ipilimumab and nivolumab were safe and well-tolerated. Overall incidence and profiles of adverse events were consistent with previous studies of ipilimumab and nivolumab combination therapy, with the exception of ocular inflammatory events, which occurred at a higher frequency in this study. 21% of patients experienced these events; most were grade 1 or 2, and all were transient. These data indicate that SCIB1 or iSCIB1+ in combination with ipilimumab and nivolumab are clinically effective and well-tolerated and has high potential to provide a meaningful clinical benefit for patients with malignant melanoma. Additional survival data from this study are maturing, and a phase 3 study as well as a study of iSCIB1+ in the neoadjuvant setting are planned.
Phase 1 study of IMA203CD8, a PRAME-targeting TCR T cell therapy for a variety of PRAME-positive solid tumors
77MO. A phase 1 trial of IMA203CD8, a PRAME-directed TCR T-cell therapy in PRAME-positive solid tumors
Antonia Busse (Charité University Medicine Berlin, Berlin, Germany) reported results from a phase 1 trial of IMA203CD8, a TCR T cell therapy with both CD8 and CD4 T cells targeting PRAME, an intracellular cancer-specific protein expressed in over 50 cancers. HLA-A*02:01-positive patients with advanced and/or metastatic PRAME-positive solid tumors underwent lymphodepletion followed by a one-time infusion of IMA203CD8 at escalating doses with or without low dose IL-2 to support T cell expansion. 78 patients were included in the safety population, and 69 patients made up the efficacy-evaluable population, which included patients with melanoma (n=42), ovarian cancer (n=11), synovial sarcoma (n=11) or other solid tumors (n=5). Patients had received a median of 3 prior systemic therapies. The most common treatment-emergent adverse events (TEAEs) were cytopenias associated with lymphodepletion. 95% of patients experienced cytokine release syndrome, but most cases were grade 1 or 2. Two patients experienced dose-limiting toxicities at dose level 4, and no grade 5 TEAEs occurred. The confirmed overall response rate was 36%, including three complete responses, two in patients with melanoma, and one in a patient with synovial sarcoma. Tumor reduction occurred in 78% of patients, the disease control rate was 84%, and responses were observed across tumor types. Responses were durable, with a median duration of response of 9.2 months, and some responses lasting over three years. IMA203CD8 is tolerable and associated with deep and durable responses, potentially representing a cancer-agnostic treatment for PRAME-expressing solid tumors. This study provides clinical proof-of-concept for targeting PRAME across a variety of tumor types in patients with limited treatment options. Dose escalation at dose level 7 (7.2 to 10 billion TCR T cells) is ongoing, and efficacy evaluations of patients treated at dose levels 6 and 7 are planned for the next year.
Safety and efficacy of CD47-targeting fusion protein HCB101 as monotherapy and in combination with standard of care therapies for solid tumors
242MO. HCB101, a differentiated SIRP alpha-Fc fusion protein, demonstrates favorable safety and early antitumor activity across solid tumors and lymphomas
Fangling Ning (Affiliated Hospital of Binzhou Medical Universtiy, Yantai, China) presented early safety and efficacy data on HCB101, an SIRP alpha – IgG4 Fc fusion protein. The SIRP alpha portion is engineered to bind to CD47, the “don’t eat me,” signal, preferentially on tumor cells and not red blood cells, thus preventing cytopenias and other hematologic toxicities. The IgG4 portion of the protein activates phagocytosis by interacting with the Fc gamma receptor on macrophages. 63 patients were treated in the phase 1a portion of HCB101 monotherapy for solid tumors and lymphomas. Of the 59 safety-evaluable patients, one patient experienced a dose-limiting toxicity, and 88.2% of patients experienced grade 1 or 2 treatment-related adverse events. 2 confirmed partial responses were observed, one with head and neck cancer and one with marginal zone lymphoma and 9 patients experienced durable stable disease lasting 4 to 9 months or longer. In phase 1b trials of HCB101 in combination with standard-of-care chemotherapy and/or immunotherapy for first- or second-line gastric cancer, or first-line triple negative breast cancer, no new safety signals were observed, no bleeding events occurred, and cytopenias were attributable to chemotherapy, not to HCB101. In patients receiving HCB101 with ramucirumab and paclitaxel for second-line gastric cancer (n=12), the disease control rate (DCR) was 100% and the objective response rate (ORR) was 58%. Activity was observed across HER2-negative and HER2-positive subtypes, and efficacy outperformed historical benchmarks. In patients receiving HCB101 with trastuzumab and platinum-based chemotherapy for first-line treatment of HER2-positive gastric cancer (n=3), one patient experienced a partial response and two experienced stable disease. In patients receiving HCB101 with chemotherapy and pembrolizumab for first-line treatment of triple negative breast cancer (n=6), DCR was 100%, and ORR was 33% with two partial responses. These data indicate that HCB101 provides cytopenia-sparing anti-CD47 therapy and clinically meaningful activity as monotherapy and in combination with standard-of-care chemotherapy and/or immunotherapy. A phase 2a study expanding use of HCB101 for gastric cancer, triple negative breast cancer, head and neck cancer, and selected immunotherapy resistance settings is planned.
Addition of retifanlimab to standard-of-care chemotherapy significantly improves survival outcomes in patients with advanced squamous anal cancer
123MO. Survival outcomes in POD1UM-303/InterAACT-2: A phase 3 study of retifanlimab (R) + carboplatin-paclitaxel (CP) in first-line (1L) advanced squamous anal cancer (SCAC)
John-Philippe Spano (Groupe Hospitalier Pitie-Salpetriere, Paris, France) reported the first overall survival (OS) data and subgroup and exploratory analyses from the phase 3 POD1UM-303/InterAACT-2 study of retifanlimab in combination with carboplatin and paclitaxel as first-line treatment for advanced squamous anal cancer (SCAC). Retifanlimab, a humanized anti–PD-1 monoclonal antibody has shown activity in platinum-refractory SCAC and cervical cancer, and retifanlimab in combination with carboplatin and paclitaxel has been approved in the United States as first-line treatment for locally recurrent or metastatic SCAC and as monotherapy for platinum-refractory SCAC. Patients with locally recurrent or metastatic SCAC were randomized to receive retifanlimab and standard-dose carboplatin-paclitaxel (retifanlimab arm; n=154) or placebo and standard-dose carboplatin-paclitaxel (placebo arm; n=154). Patients in the placebo arm had the option to cross over to the retifanlimab arm after verified progressive disease. Patients with HIV were included in the study. Previous reports indicated that the median progression-free survival (PFS) of the retifanlimab arm was significantly higher than the placebo arm at 9.3 months and 7.4 months, respectively (HR 0.63, p=0.0006), and PFS benefits associated with retifanlimab were observed in all pre-determined patient subgroups, thus the study met its primary endpoint of PFS. OS was significantly improved in the retifanlimab arm compared to the placebo arm, with median OS of 32.8 months and 22.2 months, respectively (HR 0.75, p=0.0305), and 36-month OS rates were 47.5% in the retifanlimab arm and 34.3% in the placebo arm. When adjusted for crossover from the placebo arm to the retifanlimab arm, OS benefits strongly favored the addition of retifanlimab to carboplatin and paclitaxel. Addition of retifanlimab to carboplatin and paclitaxel was well tolerated, and no new safety signals were reported. Given these significant improvements in PFS and in OS, addition of retifanlimab to carboplatin and paclitaxel represents a new standard of care for first line treatment of patients with advanced SCAC.
Post-hoc survival analysis of bifunctional fusion protein SHR-1701 with CAPOX for advanced gastric or gastroesophageal junction adenocarcinoma with high-risk features
243MO. SHR-1701 plus CAPOX for advanced gastric or gastroesophageal junction adenocarcinoma with high-risk features: Results from a phase III study
Zhi Peng (Peking University Cancer Hospital & Institute, Beijing, China) reported post-hoc analysis of a phase 3 clinical trial of SHR-1701, a bifunctional fusion protein consisting of an anti–PD-1 monoclonal antibody fused to the extracellular domain of the TGF Beta receptor II, in combination with the chemotherapy combination CAPOX as first-line therapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma (GC/GEJA). This study had previously met its primary endpoint: the addition of SHR-1701 to standard-of-care CAPOX significantly improved overall survival (OS) compared to placebo with CAPOX in a patient population with PD-L1 CPS >= 5 (HR 0.53) and the intent-to-treat population (HR 0.66). The presented analyses were performed on high-risk patient subgroups, including those with baseline liver metastases (n=351), baseline peritoneal metastases (n=247), and baseline diffuse-type histology (n=80). In the subgroup with baseline liver metastases, median OS of SHR-1701 and CAPOX was 16.8 months, compared to 10.3 months with placebo and CAPOX (HR 0.46), and survival benefits with SHR-1701 were highest among patients with high PD-L1-expressing tumors (CPS>=5; HR 0.40). Similar trends were observed in the subgroups with baseline peritoneal metastases and with diffuse-type histology. Among the subgroup with peritoneal metastases, the median OS with SHR-1701 and CAPOX was 12.6 months, compared to 8.4 months with placebo and CAPOX (HR 0.68). In the group with diffuse-type histology, median OS was 16.4 months with SHR-1701 and CAPOX, compared to 9.5 months with placebo and CAPOX (HR 0.50). For both subgroups, SHR-1701 survival benefits were greatest in patients with higher PD-L1 expression (HR 0.48 with peritoneal metastases and HR 0.27 with diffuse-type histology). Survival data were also analyzed for patients with more than one high-risk feature (n=551). In this subgroup, median OS was 14.4 months with SHR-1701 and CAPOX, compared to 10.1 months with placebo and CAPOX (HR 0.62). Survival benefits with SHR-1701 in this subgroup were comparable to the overall intent-to-treat population, and SHR-1701-associated survival benefits were greatest in patients with high PD-L1 expression (HR 0.64). These results suggest that SHR-1701 with CAPOX is associated with survival benefits in patients with GC/GEJA with high-risk features at baseline such as liver metastases, peritoneal metastases, and diffuse-type histology, especially among patients with tumors with high PD-L1 expression levels. Although some subgroups had limited sample sizes, these results suggest SHR-1701 with CAPOX represents a potential treatment option for patients with advanced gastric cancer harboring high-risk features, a patient population with poor prognosis and limited treatment options.