The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the 2024 AACR Annual Meeting. Below is a recap of highlighted research presented from Friday, April 5–Wednesday, April 10, 2024.
2024 Scientific Highlights
Long-term follow-up of CD70-targeting allogeneic CAR T cell therapy for refractory clear cell renal cell carcinoma
CT002. CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: Long-term follow-up and translational data from the phase 1 COBALT-RCC study
Samer A. Srour (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) presented long-term follow-up data from a Phase I dose-escalation study of CTX130TM, a CD70-targeting allogeneic CAR T cell therapy for patients with clear cell renal cell carcinoma (ccRCC) after prior treatments with at least one checkpoint inhibitor and a tyrosine kinase inhibitor. CTX130, which is manufactured from healthy allogeneic donors, contains TRAC and B2M disruptions to prevent graph-versus-host-disease and CD70 disruptions to augment CAR T cell function. 16 patients with stage IV disease enrolled in a dose escalation trial. Patients had received a median of 3 prior lines of systemic therapy (range 1-6) and had a median tissue CD70 expression of 100% (range 1-100%). Patients received standard lymphodepletion with fludarabine and cyclophosphamide for three days before infusion of CTX130, with doses ranging from 3x10^7 to 9x10^8 CAR T cells. Cytokine release syndrome was observed in 50% of patients, and all events were grade 1 or 2. 19% of patients experienced grade 3 infections. No instances of Immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. The objective response rate (ORR) was 6.3% with one patient (6.3%) achieving a complete response (CR) of over 36 months. 12 patients (75%) achieved stable disease (SD), with one patient experiencing SD for more than 18 months, and the disease control rate was 81.3%. Pharmacokinetic analyses indicated peak concentrations of CTX130 occurred between Days 7 to 15 post-infusion. CTX130 exhibits encouraging anti-tumor activity and a strong safety profile, and the durable CR of over three years is the first and longest observed with allogeneic CAR T cell therapy in refractory solid tumors. These results support further studies investigating CD70-targeting CAR T cell therapy for ccRCC and other CD70-expressing solid tumors. It additionally highlights the importance of building CAR T products that will be persistent and of high apheresis quality. A study of CTX131, CTX130 edited by CRISPR to disrupt Regnase-1 and THFBR2, to enhance cell potency and persistence, is in progress.
Safety and efficacy data of linvoseltamab, a BCMA-targeting bispecific T cell engager, for relapsed or refractory multiple myeloma
CT001. Linvoseltamab, a B-cell maturation antigen-targeted T-cell-engaging bispecific antibody, induces deep and durable responses in patients with relapsed or refractory multiple myeloma including difficult-to-treat subgroups
Sundar Jagannath (Icahn School of Medicine at Mount Sinai, New York, NY, USA) presented safety and efficacy results from the LINKER-MM1 clinical trial testing linvoseltamab, a bispecific antibody targeting B cell maturation antigen (BCMA) and CD3 for relapsed/refractory multiple myeloma (RRMM). The presented analysis focused on the cohort receiving a dose of 200 mg. Data from 117 patients with active MM whose disease was triple-refractory and had received a median of 5 prior lines of therapy were included in the analysis. Of note, patients median age was 70 years old (range 31-91) and 17% people of Black/African American race, appropriately reflecting the affected population. Patients received linvoseltamab weekly through week 14 then once every two weeks. Patients achieving a very good partial response or better after at least 24 weeks of treatment could transition to dosing once every four weeks (Q4W). At a median follow-up of 11.1 months, the objective response rate (ORR) was 71%. 46% of patients achieved complete remission (CR) or better. Patient responses deepened over time, including in those receiving Q4W dosing. 48% of patients with a VGPR or better achieved a response of CR or better after switching to Q4W dosing. Responses were observed across all patient subgroups, including among high-risk subgroups with stage 3 disease (ORR 62%) and with extramedullary plasmacytomas (ORR 53%). Median duration of response was not reached at time of reporting, and the estimated probability of maintaining response after 12 months was 78%. Progression free survival (PFS) and overall survival (OS) were also not reached, with a 12-month PFS probability of 69% and a 12-month overall survival probability of 75%. 46% of patients experienced cytokine release syndrome (CRS), with 35% of patients experiencing grade 1 CRS, 10% grade 2, and 1% grade 3. These rates appear lower and less severe than those traditionally observed with bi-specific antibody treatment in this population. CRS occurred mostly during step-up dosing of linvoseltamab and was quickly resolved. Infections occurred in 73% of patients, with grade 3-4 in 34% of patients. The frequency and severity of infection decreased over time, especially among patients after 6 months of Q4W dosing. The data indicate that linvoseltamab is associated with deep durable responses in a patient population with few treatment options, and adverse events are manageable and predictable, especially in comparison to other bispecific antibodies for treatment of RRMM. The phase 3 LINKER-MM3 trial of linvoseltamab for RRMM is in progress.
Oncolytic intralesional therapy for invasive cutaneous squamous cell carcinoma
CT004. A single arm phase 2 study of TVEC in patients with invasive cutaneous SCC: A novel therapeutic approach for low-risk tumors
Clara Curiel-Lewandrowski (University of Arizona, Tucson, AZ, USA) presented results from a phase 2, single-arm single-site study of talimogene laherparpvec (TVEC), an HSV-1 oncolytic intralesional therapy for the management of cutaneous squamous cell carcinoma (cSCC), specifically in patients with increased burden of primary tumors. The rationale behind this study is that T-VEC, which has been approved by the FDA for the treatment of unresectable recurrent melanoma, will destroy cancer cells through its oncolytic activity, and TVEC’s induced production of granulocyte-macrophage colony-stimulating factor (GM-CSF) will enhance anti-tumor immunity at the site of injection and at distant sites. 11 patients with at least one histologically confirmed primary low-risk cSCC were included in the study. Target lesions injected (TLI) and target non-injected lesions (TNILs) were selected, clinically measured, and partially biopsied. At TLIs, 100% of patients achieved a response, with one patient (1%) achieving a partial response and 10 patients (91%) achieving a complete response. The median time to response was 35 days, and bystander effects were observed on lesions neighboring the injection site. Adverse events were mild and transient; most events were grade 1, and one patient experienced grade 2 events. Intralesional TVEC decreased the rate of new primary cSCC tumors, but this decrease was not statistically significant. Two years after treatment, patients had a lower number of invasive sCC tumors per patient compared to one year (p=0.0156) and two years (p=0.0312) before treatment. The median number of invasive cSCC tumors decreased by 83% one year before and two years after TVEC treatment and by 75% two years before and two years after TVEC treatment. These results indicate that intralesional TVEC treatment is highly effective in treating low to intermediate risk cSCC, may produce an abscobal effect on neighboring lesions, and prevent formation of additional primary tumors, thus supporting further studies in larger cohorts of patients. Further questions, such as if this will translate to a durable decreased rate of new cSCC formation past two years and if subsequent cSCC should be treated TVEC injections are still to be answered.
Identification of patients with HR+ HER2- breast cancer who are most likely to benefit from neoadjuvant immunotherapy
1207. Immune subtyping identifies a subset of HR+HER2- early-stage breast cancer patients with a very high likelihood of response to neoadjuvant immunotherapy (IO): Results from 5 IO arms of the I-SPY2 TRIAL
Denise Wolf (University of California San Francisco, San Francisco, CA, USA) reported the performance of the 53-gene immune classifier (ImPrint) for predicting response to neoadjuvant immunotherapy (IO) in patients with early-stage hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer. The goal of the study was to identify patients with HR+ HER2- breast cancer for whom the addition of IO to a standard chemotherapy regimen would improve pathologic complete response (pCR) over chemotherapy alone. Data from 204 patients treated with paclitaxel plus one of five IO arms (anti-PD1, anti-PDL1 + PARP inhibitors, anti-PD1 + TLR9 agonist, anti PD1 +/- LAG3) and 191 patients from the control arm (chemotherapy only) of the I-SPY2 trial were included in the analysis. Following paclitaxel, all patients on trial were treated with doxorubicin and cyclophosphamide. Patients were classified as ImPrint+ (likely sensitive to IO) or ImPrint- (likely resistant to IO) using pre-treatment mRNA samples. 26% of patients with HR+ HER2- disease in I-SPY were classified as ImPrint+. Among all five IO arms (n=205 HR+ HER2- patients), 75% of ImPrint+ patients achieved a pCR, compared to 17% of ImPrint- patients. In the control arm, pCR rates were 33% and 8% for ImPrint+ and ImPrint- patients, respectively. While results indicate that chemotherapy response is more predominant in patients who are ImPrint+ compared to ImPrint- (delta-pCR rate = 25%), this difference is less dramatic compared to treatment with IO (delta-pCR rate = 55%). pcR rates were used to develop a predictive model which estimated the 5-year distant recurrence free survival (DRFS) advantage in HR+ HER2- ImPrint + patients at 91% in IO arm, compared to 80% in the control arm. ImPrint was compared to the MP2 and tumor grade (III) response predictors, and pCR prediction rates for MP2 (56%) and Grade III (45%) were considerably lower than the pCR rate for ImPrint+ (75%). The data indicate that ImPrint is a more precise predictive biomarker for neoadjuvant IO therapy benefit in patients with high-risk HR+ HER2- breast cancer, and ImPrint+ patients with HR+ HER2- breast cancer achieved pCR rates similar to those observed for neoadjuvant IO for triple negative breast cancer or HER2+ breast cancer. ImPrint is being further evaluated in the I-SPY2 trial to identify patients who are most likely to benefit from IO.
Early efficacy and safety studies of antibody drug conjugate mirvetuximab soravtansine in combination with pembolizumab for serous endometrial cancer
CT008. A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer
Rebecca Porter (Dana-Farber Cancer Institute, Boston, MA, USA) reported a phase 2, two-stage, single cohort study evaluating mirvetuximab soravtansine (MIRV), a folate receptor-alpha (FRa)-targeting antibody-drug conjugate (ADCs), in combination with pembrolizumab for patients with recurrent or persistent endometrial cancer (EC). Although immune checkpoint blockade for microsatellite stable/mismatch repair deficient (MSI/dMMR) has been successful in EC treatment, there has been a lack of immunotherapy options for ECs that are microsatellite stable/mismatch repair proficient (MSS/pMMR). This study builds upon prior studies showing that MIRV has modest single agent activity against EC, with tumor regression most often occurring in serous tumor subtypes as well as preclinical and early clinical evidence indicating ADCs may augment anti-cancer activity of immune checkpoint inhibitors. 16 patients with advanced or recurrent FRa positive, MSS/pMMR serous EC received combination treatment of MIRV and pembrolizumab every 3 weeks. At a median follow-up of 4.7 months, 6 patients (37.5%) achieved an objective response, with 1 patient achieving a confirmed completes response (CR), 5 patients achieving a partial response (PR; 3 confirmed, 2 unconfirmed), and 5 patients achieving stable disease. The 6-month progression free survival rate was 16.2%. Two patients had prolonged duration of response, with the CR over 18 months, and one PR for 11.3 months. No new safety signals were identified in the study, with most adverse events at Grades 1 or 2. Exploratory analyses to identify biomarkers of response or resistance are ongoing. Although the cohort is small, expression of FOLR1, the gene encoding FRa, is not associated with response. Although more studies are needed to identify approaches to prolong patient response to treatment, the data provide preliminary evidence that MIRV in combination with pembrolizumab is associated with clinical benefit for patients with FRa positive, MSS/pMMR, serous EC. This study also met statistical criteria to justify further evaluation of this patient population.
Atezolizumab is not associated with significant clinical benefits in patients with high-risk locally advanced squamous cell carcinoma of the head and neck after definitive local treatment.
CT009. IMvoke010: A phase III, double-blind randomized trial of atezolizumab (atezo) after definitive local therapy vs placebo in patients (pts) with high-risk locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN)
Deborah Wong (UCLA Medical Center, Los Angeles, CA, USA) presented results from IMvoke010, a phase III study evaluating the safety and efficacy of atezolizumab (atezo) in patients with locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) at high risk for disease progression after multi-modal definitive treatment. 406 patients were randomized to receive atezo (n=203) or placebo (n=203). 38.9% and 37.9% of patients in the atezo and placebo arms, respectively, underwent surgery as part of definitive treatment. 83.7% and 84.7% of patients in the atezo and placebo arms, respectively, exhibited a complete response to prior multi-modal definitive treatment. The two-year investigator-assessed event-free survival (INV-EFS) was 67.4% for the atezo arm and 63.8% for the placebo arm. At a median follow-up of 46.5 months, median INV-EFS was 59.5 months in the atezo arm, compared to 52.7 months in the placebo arm (HR 0.94). INV-EFS results were consistent across all subgroups, and no OS differences were observed between the two arms. Treatment with atezo was well-tolerated and did not reveal any new safety signals. While atezo numerically improved INV-EFS in patients with LA SCCHN, the improvement was not statistically significant. These data indicate that immune checkpoint inhibition yields limited activity in locally advanced disease settings, and the role of immunotherapy for unselected patient groups with locally advanced SCCHN remains undetermined.
Immune checkpoint blockade and HER2-targeting therapy for patients with HER2-enriched early breast cancer
CT029. Chemotherapy-free neoadjuvant regimen with durvalumab, trastuzumab and pertuzumab (DTP) in HER2-enriched early breast cancer: A prospective, open-label phase II trial
Jian Guan (Houston Methodist Neal Cancer Center, Houston, TX) presented results from a single-arm open-label phase II study of HER2-targeted therapy with trastuzumab (T) and pertuzumab (P) in combination with durvalumab (D) for previously untreated HER2-enriched breast cancer. This trial builds upon previous preclinical studies indicating a synergistic effect of immune checkpoint blockade (ICB) and HER2-targeted therapy. Patients were assessed for response after 6 cycles of DTP, and responders who were negative for residual cancer by MRI or biopsy underwent surgery. Patients with tumors non-responsive to DTP were offered salvage standard chemotherapy before surgery. After surgery, patients who achieved pathologic residual cancer burden (RCB) 0 or 1 received adjuvant DTP for one year, while patients with greater RCB scores received physician’s choice of standard of care adjuvant therapy. Among 37 patients evaluable for pathologic response after neoadjuvant therapy, 6 patients had non-responsive tumors, and 31 patients were deemed to have responsive tumors. Among patients who received DTP and surgery, 67.6% of patients achieved pathologic response, with 48.6% of patients with a pathologic complete response (RCB-0). Three patients identified as non-responders achieved RCB-0 after salvage chemotherapy, bringing the total pathologic response rate to 75.7% and the final pathologic complete response rate was 56.8%. DTP was well-tolerated, most observed adverse events were Grade 1 or 2, and no new safety concerns were observed. Tumors with larger size, high grade, and high levels of TILs were more likely to achieve pCR with DTP. Further studies to identify molecular and genetic biomarkers of response and resistance are ongoing. Results indicate that neoadjuvant treatment with DTP for HER2-enriched early breast cancer showed a high pathologic response rate comparable to chemotherapy, suggesting DTP may provide an effective alternative to standard of care chemotherapy in this patient subset.
Considerations for antibiotic dosing, the microbiome modulation, and immune checkpoint blockade for melanoma
CT030. Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity
Yongwoo David Seo (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) presented results from a multi-center randomized placebo-controlled biomarker-stratified Phase I trial of SER-401, a bacterial consortia enriched for Firmicutes spores and Ruminococcaceae for immune checkpoint blockade naive unresectable or metastatic melanoma. Previous studies have indicated that high gut microbial diversity and enrichment of certain taxa like Ruminococcaceae are associated with response to anti-PD-1 therapy for melanoma. This study investigated whether SER-401 treatment would increase the relative abundance of spore-forming bacteria, specifically Ruminococcaceae above pre-antibiotic baseline and placebo values. Patients were randomized 2:1 to the SER-401 active or placebo arm and stratified by baseline stool Ruminococcaceae abundance. Patients received an oral vancomycin (vanco) preparation and SER-401 (vanco+SER-401 arm) followed by nivolumab or placebo antibiotic and placebo (placebo arm) followed by nivolumab. 14 patients were randomized to the vanco+SER-401 arm (n=8) or to the placebo arm (n=6). In the vanco + SER-401 arm objective response rate (ORR) was 25.0% and disease control rate was 37.5% with no grade 3 or 4 treatment-related adverse events (TRAE). In the placebo arm, ORR was 66.7% and DCR was 83.3% with one TRAE. Prior to treatment patients had been stratified for Ruminococcaceae abundance in the stool, and Ruminococcaceae abundance was monitored throughout the study. In the vanco + Ser-401 arm, only patients with low baseline levels of Ruminococcaceae showed enrichment for Ruminococcaceae after SER-401 administration. One patient who achieved a complete response exhibited the lowest Ruminococcaceae abundance at baseline. Treatment with vanco was associated with major shifts in the composition of the microbiome, with depletion of Ruminococcaceae and other spore formers, followed by recovery after dosing with SER-401. SER-401 treatment was not associated with rapid increase of Ruminococcaceae above pre-vanco baseline levels. A retrospective analysis of survival and response based on Ruminococcaceae levels indicated a numeric trend toward improved progression free survival and overall survival in patients with high baseline levels of Ruminococcaceae compared to lower baseline levels, suggesting the potential importance of tailoring microbiome-based treatments to patients’ baseline levels. In the vanco + Ser-401 arm, vanco preconditioning was associated with a significant increase in ICB-resistance associated pathways (such as butyrate synthesis, p<0.0001) and a decrease in response-associated pathways, but this activity was normalized by the time of nivolumab initiation. This observation was supported by a similar increase in systemic markers of inflammation after vanco preconditioning but changes were normalized by the first dose of immunotherapy. Although study enrollment numbers were negatively impacted by the COVID-19 pandemic, these results underscore the complexities of gut microbiome modulation in patients receiving immunotherapy treatment for cancer. This study demonstrates that SER-401 and anti-PD-1 therapy are a safe combination for patients with melanoma, but more work is needed to optimize this form of treatment, specifically preconditioning and microbiome modulation strategies, as well as interventional drug dosing regimens.
Safety and efficacy of neoadjuvant immune checkpoint blockade in combination with chemotherapy for borderline resectable pancreatic cancer
CT031. A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer
Zev A. Wainberg (UCLA Medical Center, Los Angeles, CA, USA) reported clinical and pathologic results from a Phase I/II pilot clinical study of the safety and efficacy of modified FOLFIRINOX (mFFX) and nivolumab (nivo) in patients with borderline resectable (BR) pancreatic cancer (PC). Previous trials have established mFFX as a reference regimen for BRPC. Patients with BRPC received neoadjuvant treatment with mFFX and nivo, and after three months of treatment, patients underwent surgical resection if their tumors were considered resectable. 28 patients were enrolled in the study, and 22 (79%) underwent surgery. 21 of the patients who underwent surgery received R0/R1 resection. Two patients achieved pathologic complete responses, and two achieved near-complete responses. At a median follow-up of 25.6 months, median progression-free survival was 21.9 months and 27.3 months among patients who received resection. Median overall survival (OS) was 34.6 months and 44.0 months among patients who received resection. The 12-month OS rate was 82%, and the18-month OS rate was 77%, which is higher than historic controls. Prior to resection, 55% of patients experienced a grade 3 adverse event or higher, and all events were related to mFFX and not nivo. No grade 2 post-operative fistulas observed, no patients experienced severe post-operative complications. Neoadjuvant treatment with mFFX and nivo was associated with an increase in germinal centers in lymph nodes and increased numbers of tertiary lymphoid structures compared to pre-treatment baseline levels. Levels of plasma cells and CD4+ memory cells increased after neoadjuvant treatment with mFFX and nivo, and adenosine signature scores also increased after mFFX+Nivo treatment. These data support the addition of nivolumab to neoadjuvant treatment with FOLFIRINOX to improve outcomes for patients with BRPC. A follow-up study of immune checkpoint inhibition in combination with chemotherapy for neoadjuvant treatment of pancreatic cancer is in progress.
Tertiary lymphoid structures as a predictor of response to immune checkpoint inhibition for treatment of advanced solid tumors
CT033. Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort
Antoine Italiano (Institute Bergonié, Bordeaux, France) presented an open-label, phase II study of the PD-1 inhibitor avelumab combined with regorafenib, a multikinase inhibitor, in patients with mature tertiary lymphoid structure (mTLS)-positive advanced solid tumors. Tertiary lymphoid structures (TLS), which regulate anti-tumor immune responses within the tumor microenvironment, are associated with improved prognosis in several tumor types and may predict response to immune checkpoint inhibitors. 38 mTLS-positive patients were included in the study, and the five most common histological subtypes in the patient population were microsatellite stable colorectal cancer (15.8%), sarcoma (13.1%), oesogastric (10.5%) biliary tract (7.9%), and pancreatic cancer (7.9%). All patients presented at least one adverse event. 23.7% of patients presented a serious adverse event related to regorafenib and/or avelumab, but no treatment-related deaths were reported. 34 patients were evaluated for efficacy. 17 patients (50%) showed tumor shrinkage, and 12 patients (35.3%) were progression-free at 6 months. The objective response rate was 26.4%, and the median duration of response was 6 months. Responses were observed in various tumors, including those typically considered resistant to PD-(L)1 inhibition. Median progression-free survival was 3.6 months, and median overall survival was 8.6 months. Biomarker analyses are ongoing, and plasma proteomic analyses indicate several cytokines, including CSF1 and LIF, associated with primary resistance. This histology-agnostic trial leveraging TLS as a biomarker for patient selection is one of the first of its kind. Durable responses were observed in a variety of tumors, even in histological subtypes that are traditionally resistant to immunotherapy, confirming the value of TLS as predictive biomarker to identify patients more likely to respond to immune checkpoint inhibitors for advanced solid tumors. To identify additional putative biomarkers of response or resistance to immune checkpoint inhibitors, spatial transcriptomic studies of extreme responders are ongoing.
Preclinical characterization of BND-35, an anti-ILT3 antibody for remodulation of the tumor microenvironment
3920. BND-35, a novel anti-ILT3 antibody for remodulation of the tumor microenvironment
Tsuri Peretz (Biond Biologics, Misgav Industrial Park, Israel) reported the preclinical characterization of BND-35, a humanized IgG4 ILT3 antagonist antibody for the treatment of solid tumors. ILT3, an inhibitory immune receptor, is expressed in suppressive myeloid cells, including tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSCs), and tolerogenic dendritic cells (DCtol). Binding of ILT3 to its ligands mediates inhibition of T cell activity and generates an immunosuppressive tumor microenvironment. Prior studies indicate overexpression of ILT3 in myeloid cells correlates with poor prognosis for patients with solid tumors. BND-35 binds ILT3 specifically with high affinity and blocks ILT3 interaction with PAOE and fibronectin in a concentration-dependent manner. BND-35 restored a pro-inflammatory M1 phenotype in patient-derived monocytes from gastric and colon cancer tumors. BND-35 restored activity of CD4 and CD8 T cells in vitro in the presence of inhibitory DCtol, MDSCs, or M2 macrophages both as a single agent and in combination with anti-PD-1 antibodies. Blocking ILT3 activity with BND-35 induced a pro-inflammatory phenotype in T cells in a patient-derived tumoroid system ex vivo. BND-35 inhibited tumor growth in a mouse model of colon cancer, and myeloid cells and T cells from BND-35-treated mouse tumors exhibited reduced PD-L1 expression and T cell activation, respectively. BND-35 also enhanced anti-tumor activity of anti-PD-1 antibodies in a mouse model of breast cancer. Preliminary studies indicate BND-35 enhances the anti-tumor activity of other cancer therapies to restore or enhance the activity of dendritic cells, monocytes, and NK cells. These results indicate BND-35, an anti-ILT3 antagonist antibody can remodel the tumor microenvironment by inducing pro-inflammatory activity of myeloid cells and enhancing T cell activity in multiple in vitro, ex vivo, and in vivo models. The first in-human studies of BND-35 as monotherapy, in combination with cetuximab, and in combination with anti-PD-1 therapy in patients with solid tumors are set to start later this year.
Combination therapy of a histone deacetylase inhibitor with a PD-1 inhibitor remodels the tumor microenvironment of pancreatic cancer
CT016. Immunomodulation of the tumor microenvironment of pancreatic ductal adenocarcinoma with histone deacetylase inhibition: Results of a phase 2 clinical trial of entinostat in combination with nivolumab
Marina Baretti (Johns Hopkins University School of Medicine, Baltimore, MD, USA) presented results from a single center open label two-stage phase II study of entinostat, a histone deacetylase (HDAC) inhibitor, in combination with PD-1 inhibitor nivolumab in patients with advanced pancreatic ductal adenocarcinoma (PDA). This clinical trial builds upon preclinical studies indicating entinostat enhances activity of anti-PD1 immunotherapy and reduces immunosuppression within the tumor. 30 patients with metastatic or unresectable PDA enrolled in the study; more than half of the study population had received two prior lines of therapy. Of the 27 evaluable patients, the objective response rate (ORR) was 11%, with 3 patients achieving a partial response by RECIST v1.1 criteria. 2 patients achieved stable disease. The median duration of response was 10.2 months. All patients experienced toxicities, 6 patients required entinostat dose reduction, and no grade 5 events were observed. Paired analyses of tumor biopsy and peripheral blood samples indicated two weeks of entinostat treatment favorably reprogrammed myeloid cell populations in the tumor and peripheral blood, including favorable changes in dendritic cell (DC) activation, maturation, migration, and antigen processing. Two weeks of entinostat treatment was also associated with enrichment of inflammatory response signaling pathways and increased differentiation of peripheral T cells into a memory phenotype, though no increases of tumor-infiltration T cells were observed. These data provide support for the safety and clinical activity of pairing an HDAC with immune checkpoint blockade for patients with pancreatic cancer, and more studies are needed to develop approaches that enhance the clinical benefits of this combination treatment.
Cell-free tumor load dynamics as an early indicator of response or resistance to immune checkpoint inhibition for non-small cell lung cancer
6557. Longitudinal cell-free tumor load dynamics represent an early endpoint for immunotherapy response in non-small cell lung cancer
Lavanya Sivapalan (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA) presented a study investigating circulating tumor DNA (ctDNA) dynamics as an early endpoint to predict therapeutic outcomes in patients receiving immunotherapy for non-small cell lung cancer (NSCLC). Multiple studies have indicated that early decreases or elimination of ctDNA are associated with durable clinical responses to immune checkpoint blockade, while persistence or increases in ctDNA levels are associated with resistance to immunotherapy. Deep targeted sequencing of ctDNA and matched white blood cell (WBC) DNA was performed on samples from patients (n=109) who received immune checkpoint inhibitor monotherapy or immunotherapy-based combination regimen for advanced NSCLC. Over 2,800 mutations were detected, and approximately 70% were tumor derived variants. Approximately 25% of mutations were related to clonal hematopoiesis (CH). CH mutations were detected in NSCLC driver genes, occasionally at positions where tumor-derived mutations were also detected, highlighting the importance of matched WBC-informed approaches to accurately identify tumor-derived variants. ctDNA alterations reflected the genomic landscape of NSCLC, including the molecular profiles of specific histological subtypes. Baseline ctDNA was found to have prognostic value, as high maximum mutant allele frequencies (maxMAF) detected pre-treatment was associated with poor survival outcomes compared to low maxMAF pre-treatment. In contrast, no association between blood tumor mutation burden (TMB) and survival was detected. Longitudinal tracking of cell-free tumor load (cfTL) was performed on samples from 73 patients during the first 3 to 9 weeks on therapy to determine molecular responses. 25 patients were classified as achieving a molecular response (mR), with undetectable levels of cfTL in the first 3 to 9 weeks of therapy. Among patients with molecular progressive disease (mPD), cfTL was detected at every timepoint. The tumor agnostic WBC-informed approach maximized the number of cases with detectable cfTL, compared to a tumor-informed approach and a plasma only approach. Molecular response was associated with durable responses to immunotherapy. Median progression free survival among patients with mR was 26.33 months, compared to 3.42 months for patients with mPD (p = 0.0001), and median overall survival was also improved in patients with mR (46.95 months) compared to patients with mPD (11.38 months; p=0.0001). These findings support ctDNA-based molecular response within the first 3 to 9 weeks of therapy as a potential early endpoint of durable clinical response to immunotherapy for NSCLC. Tumor agnostic WBC-informed analysis of ctDNA may also provide a window of opportunity to make informed clinical decisions early in the course of treatment for NSCLC.
Correlation of ultra-sensitive ctDNA detection with radiologic response or disease progression in patients receiving immune checkpoint inhibition for advanced melanoma
6558. Ultra-sensitive ctDNA detection predicts response to immune checkpoint inhibition in advanced melanoma patients
Christoffer Gebhardt (University Medical Center Hamburg-Eppendorf, Hamburg, Germany) presented an investigation of the utility of circulating tumor DNA (ctDNA) in peripheral blood to monitor response or resistance to immune checkpoint inhibition (ICI) in patients with melanoma. 188 plasma samples were collected from 23 patients with advanced melanoma receiving ICI (ipilimumab + nivolumab combination therapy or monotherapy with pembrolizumab or nivolumab), spanning a period of up to 52 weeks. Samples were analyzed using the NeXT Personal assay, an ultra-sensitive liquid biopsy platform with ctDNA detection limits as low as 1 part per million (PPM), representing an improvement over digital droplet PCR (ddPCR), which is associated with detection limits of approximately 100 PPM. Up to 28.6% of ctDNA detections occurred at levels below 100 PPM, highlighting the importance of the ultrasensitive approach compared to ddPCR. Early increases in ctDNA from baseline to treatment cycle 3 (n=16) were prognostic of progression free survival (log-rank p=0.002) and overall survival (log-rank p=0.03). On-treatment ctDNA measures of molecular response or progressive disease correlated to radiologic response/progressive disease and were prognostic of overall survival. Longitudinal ctDNA profiling also improved the accuracy of response classification earlier in treatment. Among all ten patients who achieved a complete response (CR), radiological CR was detected after at least one on-treatment ctDNA-negative determination, with molecular CR occurring an average of 250 days prior to an imaging-based CR (median 66 days). These results demonstrate the importance and utility of ultra-sensitive ctDNA assays to track response or resistance in patients receiving ICI for advanced melanoma. A study using the NeXT Personal assay to analyze ctDNA dynamics in a patient cohort receiving adjuvant treatment with ICI for melanoma is ongoing.
Elucidating the mechanism of action of lurbinectedin in the tumor microenvironment of small cell lung cancer
6554. Lurbinectedin induces multimodal immune activation and augments the anti-tumor immune response in small-cell lung cancer
Subhamoy Chakraborty (Icahn School of Medicine at Mount Sinai, New York, NY, USA) reported results from a study evaluating the immunomodulatory effect of lurbinectedin on the immune microenvironment of small cell lung cancer (SCLC) and its anti-tumor effect with or without PD-L1 blockade. Lurbinectedin, a DNA damaging agent, is FDA-approved as a second-line treatment for SCLC, and several clinical trials are investigating the efficacy of lurbinectedin in combination with immune checkpoint blockade for extensive stage (ES-) SCLC. It is known that lurbinectedin activates cGAS-STING pathway, which activates IRF3, stimulating expression of interferons and chemokines, but less is known about its effect on the tumor immune microenvironment. Immunocompetent flank RPP (Rb1, Trp53, and p130) and RPM (Rb1, Trp53, and MYCT58A) tumor-bearing mice were treated with lurbinectedin and/or anti-PD-L1 for three weeks. While monotherapy with anti-PD-L1 was not associated with an anti-tumor response, lurbinectedin alone did show a decrease in tumor growth. Importantly, combination treatment with lurbinectedin and anti-PD-L1 was associated with an even greater amount of tumor growth inhibition. Tumors from mice in the combination treatment arm exhibited significant induction of cytotoxic CD8 T cells and reduction of exhausted and regulatory T cells. CD8 depletion ameliorated anti-tumor effects of lurbinectedin, indicating anti-tumor activity of lurbinectedin +/- anti-PD-L1 was dependent on CD8 T cell activity. Bulk RNA sequencing and reverse transcriptase- (RT-) PCR of SCLC cell lines indicated lurbinectedin treatment was associated with an increase in damage-associated molecular pattern molecules (DAMPs) associated with immunogenic cell death. Treatment with lurbinectedin increased expression of HLA-I genes in a STING-dependent manner, and in the RPP and RPM mouse models, lurbinectedin treatment was associated with a significant increase in MHC class I positive cells. These data provide insights to the mechanism of the anti-tumor effects of lurbinectedin: lurbinectedin induces the cGAS-STING pathway, inducing expression of Type-I/II interferon and chemokines and MHC class-I genes, promoting immunogenic cell death and the production of ICD-related DAMPs. Increased expression of interferon and chemokines also recruits CD8 T cells to the tumor, increasing the efficacy of anti-PD-L1 therapy. Future studies of the role of ICD-related DAMPs in anti-tumor immunity and the mechanisms behind lurbinectedin-mediated modulation of the cGAS-STING pathway and immune cells are ongoing.
Blockade of CD73 overcomes resistance of quasi-mesenchymal cell lines to anti-CTLA-4 checkpoint blockade
6556. Targeting mesenchymal tumor cell-intrinsic factors sensitizes refractory tumors to immune checkpoint blockade therapy
Kimaya Bakhle (Cornell University College of Veterinary Medicine, Ithaca, NY, USA) presented a study of epithelial-mesenchymal plasticity (EMP)-mediated immune evasion and its role in the development of resistance to immune checkpoint inhibitors in breast cancer. The epithelial to mesenchymal transition (EMT) enables carcinomas to metastasize and acquire resistance to chemotherapy, and prior studies indicate the EMT program is also associated with resistance to immunotherapies. Epithelial and quasi-mesenchymal cell lines were developed from spontaneous mammary gland tumors arising in MMTV-PyMT mice. The cell lines were reintroduced in syngeneic hosts, and the immune compositions of epithelial and quasi-mesenchymal tumors were compared. Prior studies have established that epithelial tumors recruit CD8+ T cells to the tumor microenvironment and are sensitive to anti-CTLA-4 blockade, while mesenchymal tumors are associated with immunosuppressive tumor microenvironments and resistance to anti-CTLA-4 blockade. RNA sequencing of the two cell lines and the quasi-mesenchymal tumors identified 7 immunosuppressive factors secreted by the mesenchymal cells. Each factor was knocked out by CRISPR/Cas9 in the quasi-mesenchymal cell line, and cells were implanted in mice. Knockouts of CSF1 and of SPP1 partially sensitized mesenchymal cell lines to anti-CTLA-4 blockade, and knockout of CD73 completely sensitized the cell line to anti-CTLA-4 blockade. Quasi-mesenchymal tumors knocked out for CD73 showed significant increases in CD4 and CD8 T cell infiltration compared to control tumors, suggesting that activity of CD73, which is involved in the immunosuppressive adenosine pathway, is necessary for exclusion of T cells from mesenchymal tumors. Knockout of CD73 and CSF1 also promoted infiltration of immunogenic M2 macrophages and exclusion of immunosuppressive M1 macrophages to the tumor. Quasi-mesenchymal cells were implanted in mice, and mice were treated with anti-CD73 alone or anti-CD73 in combination with anti-PD1, anti-CTLA-4, or anti-PD1 + anti-CTLA-4. Anti-CTLA-4 combined with anti-CD73 showed the most effective anti-tumor activity against quasi-mesenchymal tumors. Mining of canine mammary tumor RNA sequencing data has indicated that NMF3 subset of canine tumors associated with EMT have increased expression of CD73 and other mesenchymal markers, suggesting some mechanisms of immune evasion may translate across species. These results indicate that mesenchymal cancer cell-intrinsic factors modulate the immunosuppressive tumor microenvironment, and blockade of these factors, specifically CD73, may restore sensitivity of these tumors to anti-CTLA-4 blockade. Translational studies of these factors in human and veterinary patients are ongoing.