We are pleased to present highlights of the latest advances in immunotherapy emerging from the 2026 ASCO Annual Meeting, June 1, 2026.
(Thanks to Chinmay Jani, MD and Terri Holzen, PhD for compiling these scientific highlights)
Live biotherapeutic CBM588 improves the clinical efficacy of immune checkpoint blockade-based therapies as first-line treatment for metastatic renal cell carcinoma
4519. Microbial dysbiosis as predictor of benefit from CBM588 as an adjunct to immune checkpoint blockade-based first line therapies in metastatic renal cell carcinoma
Rahul Winayak (City of Hope Comprehensive Cancer Center, Duarte, CA, USA) reported analyses of the prognostic and predictive values of microbial dysbiosis with CBM588, a Clostridium butyricum-based live biotherapeutic used in combination with immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (mRCC). Analysis was performed on clinical outcomes of a combined cohort of two randomized phase 1 trials of CBM588 combined with ICI-based therapies as first line treatment for mRCC (NCT03829111; NCT05122546). Analysis was performed on clinical data from 59 patients with mRCC. Shotgun metagenomic sequencing data from patient stool samples were utilized to derive TOPOSCORE and baseline S scores, a stool metagenomic dysbiosis index linked to ICI outcomes. 20 patients received standard of care (SOC) treatment for mRCC, either nivolumab and ipilimumab or nivolumab and cabozantinib, and 39 patients received SOC with CBM588 (SOC+CBM588). Patients in the SOC arm had a median of 3.5 metastatic sites (ranging from 1 to 6), and patients in the SOC + CBM588 arm had a median of 3 (range 0 - 6). The most common metastatic sites in the overall patient population were lung, lymph node, and bone. CBM588 significantly improved response rate, with objective response rates of 69.2% in the SOC + CBM588 arm, compared to 20.0% in the SOC arm (p=0.001). Disease control rates were also improved at 79.5% and 45.0%, respectively (p=0.0095). Median progression-free survival (PFS) was 32.0 months in the SOC + CBM588 arm and 3.7 months in the SOC arm (p=0.001; HR 0.31, 0.16-0.62). Safety profiles were similar between the two arms, with 92.3% of patients in the SOC + CBM588 arm experiencing an adverse event (AEs) compared to 95.0% of patients in the SOC arm. 56.4% and 50.0% of AEs, respectively, were grade 3 or 4. Among patients who were SIG1+, a dysbiosis-related immune resistance phenotype, CBM588 significantly improved PFS, with median PFS of 24.9 months in the SOC + CBM588 arm (n=20) compared to 2.8 months in the SOC arm (n=8; HR 0.17; 0.05-0.54; p=0.003). CBM588 numerically improved PFS in patients who were SIG2+ (non-dysbiosis phenotype), with median PFS of 32.0 months for the SOC + CBM588 arm (n=16) and 10.9 months for the SOC arm (n=10), but this difference was not significant (p=0.328). Higher response rates trended toward higher baseline S scores, corresponding to microbial dysbiosis, in agreement with prior studies. When patients were subdivided based on SOC backbone, this association occurred primarily in patients receiving nivolumab and ipilimumab and not in patients receiving nivolumab and cabozantinib, suggesting baseline S score may be more closely associated with response in patients receiving dual immunotherapy regimens compared to immunotherapy-targeted therapy combinations. These data indicate that the probiotic CMB588 improves clinical outcomes while maintaining a manageable safety profile in patients receiving first-line standard of care therapy for mRCC, specifically in patients with microbial dysbiosis. The first-of-its-kind phase 3 SWOG S2419 BIOFRONT study (S2419; NCT07383441) investigating gut microbiome intervention with CMB588 as part of a cancer therapy regimen for mRCC is currently enrolling patients.
To learn about the effects of dysbiosis on outcomes in patients receiving bispecific antibodies for multiple myeloma, read this paper from Corona et al in JITC.
Adjuvant pembrolizumab with or without radiotherapy for resected Merkel cell carcinoma
LBA9505. Updated outcomes from STAMP: Surgically treated adjuvant Merkel cell carcinoma with pembrolizumab, a phase 3 trial - ECOG-ACRIN EA6174
Janice M. Mehnert (New York University School of Medicine, New York, NY, USA) reported new analyses of Merkel cell carcinoma (MCC) specific outcomes and radiation therapy (RT) effects from the ECOG-ACRIN EA6174 study (Surgically Treated Adjuvant Merkel cell carcinoma with Pembrolizumab; STAMP), the first randomized phase 3 trial of adjuvant pembrolizumab in resected Merkel cell carcinoma- (MCC-). Eligible patients had surgically resected MCC (stage I without sentinel lymph node biopsy to IIIB) that was completely resected. Patients were randomized to receive pembrolizumab every 3 weeks for 17 cycles (n=147; Pembro Arm) or regular observation, the current standard of care (n=146; SOC Arm). RT was allowed for both arms. The co-primary endpoints were recurrent free survival (RFS) and overall survival (OS),and the secondary endpoints were distant metastasis-free survival (DMFS), safety, and tolerability. The study population was predominantly composed of patients with stage III disease (84.3%), males (68%), and White individuals (97.5%). The median age was 69 years (range, 32-97), and the majority of patients (80.2%) either received or were intended to receive radiotherapy. Primary RFS (relapse due to recurrence or death due to any cause) was improved by adjuvant pembro (24-month RFS 72%) compared to SOC (24-month RFS 66%, but the difference between arms was not statistically significant (log-rank P = 0.102). Primary DMFS was significantly improved by adjuvant pembro, compared to the SOC Arm, with 18-month DMFS rates of 87% and 80%, respectively (HR 0.58; 90% CI 0.35, 0.96; log-rank P = 0.035). As of the data cutoff, very few deaths occurred (23 deaths in the Pembro Arm and 15 deaths in the SOC Arm) so OS data are immature. When analyzing MCC outcomes, events that were specific to MCC, neoadjuvant pembro significantly improved MCC-specific PFS compared to the SOC, with 24-month PFS rates of 77% and 67%, respectively (HR 0.65, 95% CI 0.41, 1.01; log-rank P = 0.064). For patients in the Pembro Arm, RT was permitted to be concurrent (RT received on trial) or sequential (RT received prior to enrollment). For patients in the Pembro Arm, sequential RT was defined as beginning pembro treatment within 42 days of RT completion. 86.7% of the overall patient population (n=131 in the Pembro Arm, n=123 in the SOC Arm) received RT. In the Pembro Arm, 63 patients received sequential RT, and 68 patients received concurrent RT. In the SOC Arm, 58 patients received sequential RT, and 65 patients received concurrent RT. Among patients who received sequential RT, adjuvant pembrolizumab significantly improved primary RFS (HR 0.48; 90% CI 0.28, 0.84) and primary DMFS (HR 0.24; 90% CI 0.10, 0.62) compared to the SOC Arm. Primary RFS and DMFS were not significantly different between the two arms in the patient subgroup who received concurrent RT. The safety profile was manageable: 31% of patients in the Pembro Arm and 4% of patients in the SOC Arm experienced a grade 3 or higher treatment-related adverse events (TRAE) related to pembro or RT. Decreased lymphocyte count was the most common TRAE in both arms. One Grade 5 TRAE, pneumonitis, occurred in the Pembro Arm. STAMP is the largest study to date conducted in patients with MCC, and these results indicate that adjuvant pembrolizumab is associated with meaningful improvements in MCC-specific RFS and DMFS. Adjuvant pembrolizumab may also provide more benefit to patients when delivered sequentially after RT, compared to concurrent administration, aligning with past studies of immunotherapy and RT. Although more time is needed for survival data to mature, this study has the potential to inform future adjuvant immunotherapy regimens to prevent recurrence in patients with resected MCC.
Updated efficacy and safety results from Agni-01: Engineered TIL OBX-115 therapy for advanced melanoma
9507. OBX-115 engineered tumor-infiltration lymphocyte (TIL) cell therapy with regulatable membrane-bound IL15 (mbIL15) in patients with advanced melanoma that has progressed on/after immune checkpoint inhibitors: Phase 2 results
Allison Betof (Stanford University School of Medicine, Stanford, CA, USA) presented updated results of the multicenter phase 1/2 Agni-01 study (NCT06060613), investigating the engineered tumor infiltrating lymphocyte (TIL) therapy OBX-115 in patients with advanced non-uveal melanoma that progressed on or after immune checkpoint blockade. OBX-115 TIL are engineered to express membrane-bound IL15 (mbIL15) via administration of the small-molecule drug acetazolamide (ACZ), abrogating the need for high-dose IL2 after TIL therapy. ACZ induces expression of mbIL15 on the surface of OBX-115, activating the OBX-115 TIL in cis and activating other immune cells. Other clinical advantages associated with OBX-115 include a less invasive tumor tissue procurement (TTP) by core needle biopsy, low dose lymphodepletion compatible with outpatient administration, ACZ driving mbIL15 expression, and regulatable and reinducible TIL expansion and persistence. Earlier reports of Agni-01 indicate promising safety and efficacy at the recommended phase 2 dose (RP2D) and 500 mg ACZ per day. After TTP by core needle biopsy, patients underwent low dose lymphodepletion (cyclophosphamide 75 mg/m^2 x 3 days and fludarabine 30 mg/m^2 x 4 days) on an in-patient or outpatient basis. Patients were infused with OBX-115 at the RP2D (100 x 10^9 cells maximum), followed by AZD 500 mg/day orally with split dosing on days 0 to 6 and days 14 to 20. OBX-115 manufacturing incorporated an anti-4-1-BB agonist antibody to promote T-cell proliferation and generate stem-like, tumor-reactive CD8+ T cells, mbIL15 transduction with a retroviral vector, and iFeeder cells expressing IL21 and 4-1BBL to promote proliferation of active, CD8+ enriched, non-exhausted T cells. The OBX-115 infusion product contains a median of 98% CD8+ T cells. 20 patients were infused with OBX-115, and 15 received the RP2D. Of the 15 patients who received the RP2D, 4 underwent lymphodepletion on an outpatient setting, and all patients received ACZ redosing in an outpatient setting. 9 of the 15 patients had cutaneous melanoma, 3 had mucosal melanoma, and 3 had acral melanoma. 3 patients had brain and/or liver lesions and patients had received a median of two prior lines of immune checkpoint inhibitor therapy. Out of 15, 14 (93%) had progressed on anti-PD-1 combination therapy, and 11 (73.3%) had progressed on anti-PD-1 + anti-CTLA-4 therapy. At a median follow-up of 18.6 weeks (range 10.1 – 73.4 weeks), the objective response rate was 67%, with 2 complete responses and 8 partial responses. The disease control rate was 93% (14/15), and 80% of patients achieved at least 30% tumor reduction. Early data suggest responses are durable, with the median duration of response not reached. The longest patient response has lasted 14.9 months, and it is ongoing. Responses occur early, by 6 weeks after infusion, and responses deepen over time. Responses have occurred across key disease subgroups, including BRAF-mutated melanoma, prior exposure to anti-PD-1 + anti-CTLA-4, and disease with primary resistance to immune checkpoint blockade. One patient has experienced disease progression in the central nervous system, the primary disease site. Most treatment-related adverse events were grade 2 or lower and occurred in the first two weeks of infusion. Non-hematologic toxicities of grade 3 or higher were rare. Cytokine release syndrome (CRS) was reported in 5 patients, and one event was grade 3. Grade 3 febrile neutropenia occurred in one patient. No dose-limiting toxicities, immune effector cell-associated neurotoxicity syndrome (ICANS) events, or ICU transfers occurred. Longitudinal ACZ redosing was well tolerated in outpatient setting with no treatment related mortality. OBX-115 exhibited favorable cytokine and circulating tumor (ctDNA) profiles. IL-15 levels increased after lymphodepletions, as expected, but they did not elevate further after OBX-115 infusion. IL-6 levels remained well below the range associated with CRS, and ctDNA levels were reduced by day 14 after infusion in all responders including 3 with ctDNA clearance. Although longer follow-up and larger patient populations are needed to validate these results and determine long-term benefits and safety, OBX-115 continues to exhibit promising early clinical efficacy and a favorable safety profile compared to other TIL therapy regimens. With its low-dose lymphodepletion regimen, options for outpatient administration, and elimination of IL-2 in the treatment regimen, OBX-115 has high potential to broaden the population of patients who are eligible for TIL therapy.
For a recent, comprehensive overview of TIL therapy toxicities, read this review article by Woodford et al in JITC.
Pembrolizumab in combination with a PARP inhibitor as maintenance therapy for metastatic pancreatic cancer with germline BRCA2 or BRCA2 mutations
4012. Randomized phase 2 trial of olaparib and pembrolizumab vs olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 mutations (gBRCA1/2): SWOG S2001
Vincent Chung (City of Hope Comprehensive Cancer Center, Duarte, CA, USA) presented a report on SWOG S2001, a randomized phase 2 trial evaluating the combination of pembrolizumab and the PARP inhibitor olaparib as maintenance therapy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) with germline BRCA1 or BRCA2 mutations (gBRCA1/2). Previous preclinical studies suggest that PARP inhibitors modulate the tumor immune microenvironment with upregulation of tumor PD-L1 and activation of the cGAS-STING pathway. The phase 2 POLAR trial (NCT04666740) has also demonstrated promising results with pembrolizumab and olaparib as maintenance therapy in patients with homologous recombination-deficient metastatic pancreatic cancer. In the SWOG S2001 trial, patients with metastatic PDAC and pathogenic gBRCA1/2 mutations were randomized to receive olaparib and pembrolizumab (olaparib 300 mg PO BID + pembro 200 mg IV q21d x 18 doses, then 400 mg q6w; olaparib + pembro; n=34) or standard of care treatment with olaparib (olaparib; n=34). The primary endpoint was progression-free survival (PFS) with secondary endpoints of overall survival (OS), objective response rate (ORR), duration of response (DoR), and safety. Patient characteristics were mostly balanced between treatment arms, although 82% of patients in the olaparib arm received 5-fluroruracil-based chemotherapy, compared to 76% in the olaparib + pembro arm. A larger proportion of patients in the olaparib arm (47%) also achieved a partial response to first-line chemotherapy, compared to the olaparib + pembro arm (32%). No unexpected adverse events (AE) were observed. The most common hematologic AE was anemia, and grade 3 or higher anemia was experienced by 12% of patients in the olaparib + pembro arm and 13% of patients in the olaparib arm. One grade 4 treatment-related AE occurred in each arm, and 4 patients in the olaparib + pembo arm discontinued treatment due to toxicity. Some clinical benefits were observed in the olaparib + pembro arm, including an ORR of 28% in the olaparib + pembo arm versus 18% in the olaparab arm and median PFS of 8.2 months and 6.4 months, respectively. No significant survival benefits were observed, and the trial was discontinued early for futility. Factors that contributed to futility may have included under-enrollment and the choice of anti-PD-1 therapy. Past studies suggest anti-CTLA-4 may be more effective against PDAC by reducing levels of intratumoral regulatory T cells. Correlative analyses will be performed on tissue and blood samples collected during the trial will be performed and reported at a later date.
A PD-1 x TIGIT bispecific antibody in combination with bevacizumab as first-line therapy for advanced hepatocellular carcinoma
4014. Nilvanstomig (ZG005), an anti-PD-1/TIGIT bispecific antibody, plus bevacizumab vs. sintilimab plus bevacizumab biosimilar as first-line therapy for advanced hepatocellular carcinoma: A randomized, multi-center phase 2 trial
Hong Wu (West China Hospital, Sichuan University, Chengdu, China) reported results from a multi-center phase 2 trial comparing nilvanstomig (ZG005), a recombinant bispecific antibody targeting PD-1 and TIGIT, in combination with anti-VEGF antibody bevacizumab to the anti-PD-1 antibody sintilimab plus a bevacizumab biosimilar for first-line therapy for advanced hepatocellular carcinoma (HCC). PD-(L)1 inhibitors in combination with VEGF blockade is a first-line regimen for unresectable HCC, but the clinical benefits are not durable in all patients. TIGIT is a co-inhibitory receptor and immune checkpoint expressed on activated T cells, NK cells and regulatory T cells and is implicated in HCC pathogenesis. ZG005 has been shown to activate T cells and enhance the anti-tumor activity of NK cells by blocking pathways. Patients with unresectable or metastatic HCC and no prior systemic treatment were randomized to three treatment arms. Patients in Arm A (n=31) received ZG005 (10 mg/kg) plus bevacizumab (15 mg/kg). Patients in Arm B (n=32) received ZG005 (20 mg/kg) plus bevacizumab (15 mg/kg). Patients in Arm C (n=32) received sintilimab (200 mg) plus the bevacizumab biosimilar (15 mg/kg). The primary endpoint of the study was progression-free survival (PFS) per RECIST v1.1. Key secondary endpoints were PFS per mRECIST, objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and per mRECIST, and safety. Patient characteristics at baseline were balanced between treatment arms. At a median follow-up of 8.18 months for Arm A, 8.54 months for Arm B, and 9.69 months for Arm C, ZG005 + bevacizumab was associated with improved PFS compared to sintilimab + bevacizumab biosimilar. Median PFS was not reached for Arm A, 11.20 for Arm B, and 6.74 months for Arm C. The hazard ratio (HR) for Arms A and C was 0.41 (95% CI 0.18, 0.89; p=0.020), and the HR for Arms B and C was 0.35 (95% CI 0.15, 0.76; p=0.009). Per RECIST v1.1 criteria, the objective response rate (ORR) was 38.7% for Arm A, 40.6% for Arm B, and 34.4% for Arm C; DCR was 90.3%, 90.6%, and 75.0%, respectively. Per mRECIST criteria, ORR was 61.3% for Arm A, 53.1% for Arm B, and 40.6% for Arm C; DCR was 93.5%, 90.6%, and 75.0%, respectively. The safety profile of ZG005 with bevacizumab was manageable. Treatment-emergent adverse events (AEs) occurred in 100% of patients in Arms A and B and 96.9% of patients in Arm C. No patient deaths occurred, and 2 patients in Arm A and 1 patient in Arm C experienced an immune-related AE of grade 3 or higher. Proteinuria was the most common treatment-related AE for Arms B (50%) and C (40.6%). Based on its increased efficacy and manageable safety profile, ZG005 at a dose of 20 mg/kg was selected for further investigation. With these significant improvements in PFS and manageable safety profile, ZG005 in combination with bevacizumab represents a promising first-line therapy option for patients with advanced HCC. A phase 3 trial of ZG005 in combination with bevacizumab for advanced HCC is currently being planned.
Identifying tumor microenvironment-based factors that affect response to TIL therapy
9511. Immunologic determinants in procured melanoma tissue as drivers of durable response to tumor-infiltrating lymphocyte therapy
Lilit Karapetyan (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA) presented spatial and histopathologic analyses of melanoma specimens to identify features of the tumor microenvironment (TME) that are associated with durable clinical benefit and improved survival after tumor infiltrating lymphocyte (TIL) therapy. Patient data were pooled from multiple clinical trials of TIL therapy for advanced melanoma performed at the Moffitt Cancer Center. Data from 60 patients were analyzed. 19 patients participated in a trial of TIL only, 13 in a trial of TIL with ipilimumab, 11 in a trial of TIL with nivolumab, and 17 in a trial of TIL with vemurafenib. 50 of the patients were infused with TILs, and samples from 45 patients were available for pathological assessment. The rate of responses that lasted 12 or more months for the 50 patients who received TIL infusion was 36%. Response rates for individual trials ranged from 33% to 36%. Tumor harvest sites for TILs included subcutaneous/soft tissue (78%), liver (18%), and lung (4%), and tumor harvest site was not associated with TIL yields or patient response rates. Only 2 cases of manufacturing failure were represented in this study, so the impact of factors associated with manufacturing failure could not be assessed in this study. Pathological analyses of baseline samples indicated that tumors were 85% viable (IQR 60, 95), 5% necrotic (IQR 0,20), and fibrosis and melanophagocytosis were not detected. None of these pathologic features were associated with TIL expansion yield or with clinical response. 56% of tumors (n=25) contained tertiary lymphoid structures (TLS), which were associated with response to TIL therapy. Among all tumor samples, the response rate was 56% in tumors that contained TLS, compared to 20% in tumors that did not contain TLS (p=0.01). Among tumors from subcutaneous/soft tissue (n=35), the response rate in tumors that contained TLS was 68%, compared to 25% in tumors that did not contain TLS (p=0.01). The presence of TLS significantly improved progression-free survival (p=0.01) and overall survival (p<0.01) compared to the absence of TILs. The presence of TLS had no effect on TIL yield, but TILs expanded from TLS-positive tumors contained higher proportions of CD8+ T cells, compared to TILs expanded from TLS-negative tumors (p=0.03). Spatial transcriptomic studies indicated that tumors from TIL responders demonstrated upregulation of gene pathways involved in inflammatory signaling, antigen presentation, and immune activation. Patient-level immune response scores developed from spatial transcriptomic data strongly correlated with patient response (p<0.0001) and improved PFS (p<0.0001). Immune response scores also correlated with responders and non-responders from an external TIL therapy cohort (Lauss et al. 2017). These results indicate that the tumor immune microenvironment of procured tumor tissue does influence patient response to TIL therapy. Both tertiary lymphoid structures within the procured tumor tissue and spatial biology-based immune response scores were associated with response to TIL therapy and survival benefits. Although larger sample sizes should be analyzed to validate these findings, these results support the integration of tumor microenvironment-based biomarkers into strategies for patient selection and optimization of TIL therapy.