Development of QVT Score, a novel radiomic predictive biomarker of immunotherapy response and early survival outcomes in non-small cell lung cancer
66. QVT Score, a radiomic biomarker of tumor vascularity, enables immune checkpoint inhibitor (ICI) outcome prediction and early survival assessment in NSCLC
Young Kwang Chae (Northwestern University, Chicago, IL, United States) presented the development of QVT Score, a novel radiomic biomarker of tumor vascularity, to predict immunotherapy response and survival outcomes in non-small cell lung cancer (NSCLC). This work builds upon previous studies of the relationship between tumor angiogenesis and immunotherapy response and resistance, including the finding that abnormal tumor vasculature promotes hypoxia and immune exclusion, contributing to poor response to immune checkpoint inhibitors. Quantitative Vessel Tortuosity (QVT), a biomarker of tumor-associated vasculature, utilizes data from standard of care radiology scans and incorporates over 900 measurements of blood vessel branching, curvature, and twistedness. QVT score is a single, interpretable radiomic biomarker that summarizes all vascular measurements, and higher QVT Scores indicate increased vascularity. The discovery cohort consisted of 375 patients who received immune checkpoint inhibitor (ICI) monotherapy for NSCLC. The external validation cohorts included 172 patients who received ICI monotherapy for NSCLC and 135 patients who received chemotherapy and ICIs for NSCLC, and the longitudinal validation cohort consisted of 143 patients who received ICI monotherapy for NSCLC. Automatic artificial intelligence was used to analyze radiographic scans from the discovery cohort (n=375) and map lesions and surrounding blood vessels. Two distinct phenotypes were derived from unsupervised clustering, and regularized logistic regression was used to develop a continuous QVT score, ranging from 0-1, based on the severity of tumor vascularity. Overall survival (OS) data from external validation cohorts indicated that baseline QVT score could predict OS outcomes. In the validation cohort that received ICI monotherapy, median OS was 14.0 months in patients with a high QVT score and not reached in patients with a low QVT score (HR 2.07, p=0.0022). A significant association was also seen in patients who received chemotherapy and ICIs. OS among patients with a high QVT Score was 13.9 months, compared to 31.6 months in patients with a low QVT Score (HR 2.77, p=7.7 x 10-5). QVT Score was independent of other PD-L1 and other clinical variables. Longitudinal QVT scores, representing changes in QVT scores from baseline to the first follow-up scan, were calculated for patients receiving ICI monotherapy. Decreasing longitudinal QVT Scores, indicating response to immune checkpoint inhibitors was associated with improved OS (median OS 22.2 months), whereas increasing longitudinal QVT Score was associated with increased risk of death (median OS 9.0 months, HR 1.93. p=0.0022). The association of longitudinal QVT scores with OS was independent of radiographic response and overall response. QVT Score was also found to be associated with the biology of resistance to immune checkpoint inhibitors. Tumors with low pre-treatment QVT Score had a low necrotic cell density, and this association was statistically significant (r=0.40, p=0.024). Although additional studies are needed to determine its relevance to other cancer indications, QVT Score potentially represents a novel biomarker that can be used at baseline and early in treatment to predict survival outcomes and inform treatment decisions.
Myeloid expression of S100A8/9 drives immune evasion and T cell dysfunction in STK11-deficient NSCLC
706. Lineage plasticity influences immune evasion through distinct mechanisms in STK11-deficient NSCLC, with myeloid S100A8/A9 pathway driving T-cell dysfunction in poorly differentiated TTF1-low tumors
Jacob Kaufman (James Cancer Center Ohio State University, Columbus, OH, United States) presented data pertaining to the loss of STK11 and its effects on tumor biology. STK11 is a serine threonine kinase that is lost in 20 to 25% cases of lung adenocarcinoma. Loss of STK11 is associated with resistance to immunotherapy, and loss of both STK11 and transcription factor TTF1 results in increased lineage plasticity/tumor heterogeneity, which can influence the composition of the tumor microenvironment (TME). Genetically engineered STK11 mutant and STK11 wild type mouse models were generated. Orthotopic allografts from these mouse STK11 cell lines expressed elevated levels of CXCR2 and S100A8/A9, inflammation markers of polymorphonuclear neutrophils (PMNs), compared to STK11 wild type models. In STK11 mutant cell lines where wild type STK11 was restored, PMN abundance remained, but S100A8/A9 expression in PMNs decreased. STK11 mutant tumors contained a high fraction of CD44-low hypoactivated T cells, and restoring STK11 wild type significantly attenuated this phenotype. High expression of S100A8/9 by PMNs in STK11 mutant tumors was also associated with increased levels of naïve T cells. Treatment with S100A8/A9 inhibitor tasquinimod, resulted in increased levels CD8 T cell activation and decreased levels of intratumoral naïve T cells. Clinical data indicates that in immunotherapy naïve populations, high S100A8/A9 expression is associated with poor response and survival with atezolizumab for STK11-low tumors, but high S100A8/A9 expression does not affect outcomes in tumors expressing high levels of STK11. These data support a model in which epigenetic dysregulation in STK11-low tumors is directly related to increased expression of inflammatory cytokines and S100A8/A9, recruitment of PMNs and other immunosuppressive myeloid cells, causing immune evasion and T cell dysfunction, and resistance to immune checkpoint inhibitors.
Myeloperoxidase promotes immunosuppression in the tumor microenvironment of pancreatic ductal adenocarcinoma
784. Myeloperoxidase drives tumor-associated neutrophil immunosuppression and limits treatment response in pancreatic ductal adenocarcinoma
Angisha Banshet (West Virginia University, Morgantown, WV, United States) presented a study of myeloperoxidase in immunosuppression and immunotherapy response in pancreatic ductal adenocarcinoma (PDAC). PDAC is a lethal disease with a 5-year survival rate less than 13%. Treatment options for PDAC are limited treatment, in part due to an immunosuppressive tumor microenvironment. Increased production of reactive oxygen species contributes to immunosuppression in PDAC tumors, and myeloperoxidase(MPO), an enzyme primarily found in neutrophils is a major source of ROS. This study addressed the hypothesis that inhibition of MPO would overcome the immunosuppressive TME and enhance treatment response in PDAC. Pancreatic tissue samples from patients with PDAC expressed significantly higher levels of MPO compared to non-cancerous tissue samples. Murine models of PDAC exhibited significantly increased levels of MPO activity compared to tumor-free controls. PDAC tumor growth was delayed in MPO-deficient mice and in mice treated with the MPO inhibitor verdiperstat. PDAC tumors of MPO-deficient mice showed increased infiltration with neutrophils, cytotoxic NK cells, and activated and cytotoxic T cells compared to PDAC tumors from wild type mice. Depletion of NK cells or CD8 T cells in MPO-deficient mice resulted in wild-type levels of PDAC tumor growth, indicating anti-tumor effects of MPO deficiency are dependent on NK cells and CD8 T cells. PDAC tumors from MPO-deficient mice also exhibited significantly reduced levels of collagen and increased sensitivity to gemcitabine, compared to tumors from wild type mice, and similar effects were observed in verdiperstat-treated mice. In human patients with PDAC, elevated MPO activity was associated with resistance to chemotherapy. These results indicate MPO plays a critical role in promoting immunosuppression in the tumor microenvironment of PDAC, and it may serve as a potential predictive biomarker of response to cancer treatment.
Efficacy and safety results from a phase 1 study of STK-012, a partial IL-2 agonist in combination with pembrolizumab and chemotherapy for first-line treatment of PD-L1 negative non-squamous non-small cell lung cancer
1345. Initial phase 1a/1b results of STK-012, an α/β IL-2 receptor biased partial agonist, with pembrolizumab, pemetrexed, and carboplatin in 1L PD-L1 negative non-squamous NSCLC
Adam Schoenfeld (Memorial Sloan-Kettering Cancer Center, New York, NY, United States) reported results from a phase 1a/1b trial of STK-012 combined with pembrolizumab and chemotherapy in patients with treatment-naïve stage 4 non-squamous non-small cell lung cancer (NSCLC) without actionable genetic alterations. Chemoimmunotherapy has become the standard of care for first-line treatment of non-squamous NSCLC. However, approximately one-third of patients have PD-L1-negative tumors (TPS<= 1%) and derive less benefit from chemoimmunotherapy. STK-012 is a first-in class recombinant IL-2 alpha/beta-biased partial agonist that selectively binds and stimulates antigen-activated T cells. STK-012 binds less readily to lymphocytes that express the dimeric IL-2 receptor and does not interact with NK cells and naïve T cells, therefore avoiding the severe toxicities associated with high-dose IL-2. Phase 1a of the study tested STK-012 with pembrolizumab, pemetrexed, and carboplatin in PD-L1 unselected patients with treatment naïve stage IV non-squamous NSCLC, and Phase 1b tested the combination in patients with treatment naïve stage IV non-squamous NSCLC with PD-L1 TPS < 1%. No dose-limiting toxicities were observed in the safety evaluable patient population (n=25) at a median follow-up of 3.12 months. The most common treatment-related adverse events (TRAEs) were nausea, fatigue, and rash, which were manageable and reversible. One grade 4 case of neutropenia occurred, and no grade 5 adverse events occurred. Transaminitis in 8 patients was the only hallmark IL-2 toxicity observed. TRAEs led to dose reduction in one patient, and no TRAEs led to dose discontinuation. Among the 22 efficacy evaluable patients, 18 had PD-L1 <1%, and 4 patients had PD-L1 expression of 1%. At a median follow-up of 4 months, the objective response rate (ORR) was 55% for all patients and 50% among patients with PD-L1<1% tumors. The disease control rate was 96% in the entire patient population and 94% in the PD-L1<1% patient population. 14 patients experienced deepening responses over time, and responses were ongoing in 15 of 22 patients. Target lesions were reduced by a median of 16.2% at week 6 of treatment and by a median of 32.4% at week 12. 70% of patients enrolled in the study had loss of function mutations in tumor suppressor genes or a mucinous histology, which are both associated with primary resistance to immunotherapy. Although the patient populations were small, the ORR was 55% in patients with one or more tumor suppressor gene mutation (n=11), and 75% in patients with two tumor suppressor gene mutation (n=4). Responses occurred in patients with triple co-mutations (KRAS Q61H, STK11, KEAP1) and in 4 of 5 patients with cancer with mucinous histology. Peripheral blood draws at time points indicated robust and sustained induction of INF gamma, limited expansion of NK cells and regulatory T cells (due to the selective nature of STK-012), and marked expansion of CD8 and CD4 T cells, including those with markers of activation. STK-012 in combination with pembrolizumab, pemetrexed, and carboplatin demonstrated a manageable safety profile and promising results in a difficult-to-treat patient population, including patients with PD-L1 negative tumors and tumors that are typically resistant to immunotherapy. A randomized global phase 2 trial of pembrolizumab, pemetrexed, and carboplatin with or without STK-012 for first-line treatment of PD-L1<1% non-squamous NSCLC has been initiated.
Development of a novel platform to engineer effective cellular therapies against solid tumors
314. Cytokine-cell conjugates for engineered T cell therapy
Wenjian Wang (The Scripps Research Institute, La Jolla, CA, United States) presented a novel cytokine-cell conjugate (CCC) platform to locally deliver cytokines on the surface of infused T cells and enhance the efficacy and safety of adoptive cellular therapies for solid tumors. Fucosyltransferase from H. pylori was used to conjugate GDP- cytokine fusions to glycans on the surface of P14 CD8 T cells that express the T cell receptor specific for the GP33 peptide of lymphocytic choriomeningitis virus (LCMV). A CCC library was generated, and individual CCCs were assayed for increased proliferation and cytotoxicity. CD8 T cells conjugated with Neo4, an engineered cytokine that interacts with the IL-4 receptor, exhibited significantly higher cell expansion rates and cytotoxicity and reduced apoptosis compared to unmodified CD8 T cells. In comparison to unmodified CD8 T cells, Neo4-conjugated CD8 T cells exhibited increased expression of activation markers CD69 and CD25, increased granzyme production, and decreased expression of exhaustion markers such as PD-1. Neo4-conjugated T cells also exhibited high metabolic fitness, including increased levels of glycolysis and oxidative phosphorylation. Neo4-conjugated T cells showed superior cytotoxic activity and increased expansion rates compared to T cells genetically engineered to secrete Neo4 or express membrane-bound Neo4. In mouse tumor models, Neo4-conjugated P14 T cells exhibited decreased tumor growth, increased survival, and superior T cell-mediated anti-tumor immunity compared to unmodified P14 T cells. When combined with anti-CTLA4 antibodies, Neo4-conjugated P14 cells exhibited durable tumor regression, increased survival, and resistance to tumor rechallenge with B16 cells that do not express GP33. Neo4-conjugated T cells also mitigated some irAEs associated with CTLA-4 blockade. Neo4-conjugated T cells exhibited selective infiltration to the tumor and spleen and not to skin, thus providing a potential mechanism behind the minimization of off-tumor toxicities. These results provide a novel scalable method to develop and identify more effective adoptive cellular therapies that provide safer and more durable anti-cancer activity against solid tumors.
COVID-19 mRNA vaccines are sensitize tumors to immune checkpoint blockade
419. SARS-CoV-2 mRNA vaccines sensitize immunologically “cold” tumors to immune checkpoint blockade
Adam Grippin (The University of Texas MD Anderson Cancer Center, Houston, TX, United States) presented a retrospective study investigating the association of mRNA vaccines encoding non-tumor-specific antigens and response to immune checkpoint inhibitors. Although personalized mRNA cancer vaccines can sensitize tumors to immune checkpoint blockade, they are expensive and slow to produce and not well understood. This study explored whether COVID-19 mRNA vaccines could act as immune agonists and prime T cells to respond to immune checkpoint blockade in patients with cancer. Clinical data from 2406 patients who received immune checkpoint inhibitors (ICIs) with stage III or IV non-small cell lung cancer indicated that overall survival (OS) improved in patients who received a COVID-19 mRNA vaccine within 100 days of initiating treatment with ICIs compared to those who did not receive a COVID mRNA vaccine (HR 0.51, p=6.24 x 10-5). This relationship persisted in subgroups of patients with unresectable stage III NSCLC, stage IV NSCLC, and propensity score matching confirmed this association. This association was specific to treatment with ICIs and for COVID-19 mRNA vaccines; no associations were observed among patients receiving chemotherapy for NSCLC or for patients who received a non-mRNA vaccine. The association of COVID-19 mRNA vaccines with improved survival was also observed in analyses of 757 patients who received ICIs for metastatic melanoma (HR 0.37, p=0.0048), and improved progression-free survival was also associated with COVID-19 mRNA vaccination in this cohort. In a broad cohort of patients receiving ICIs for cancer, survival advantage was concentrated in patients who received a COVID mRNA vaccine within 30 days of initiating ICIs. In preclinical mouse tumor models, lipid nanoparticles containing mRNA encoding the COVID-19 spike protein (spikeRNA-LNPs) significantly slowed tumor growth when added to PD-1 blockade. SpikeRNA-LNPs were associated with large surges in IFN-alpha production in mice, and both LNPs and mRNA were required for this effect. The therapeutic benefit with spikeRNA-LNPs was dependent on IFN-alpha signaling, and spikeRNA-LNPs were also associated with increased levels of myeloid cells and antigen presentation to T cells. SpikeRNA-LNPs were also associated with increased infiltration of activated anti-tumor T cells to the tumor. Upregulated cytokines, specifically a 250-fold increase in IFN-alpha, were also observed in human volunteers who received a COVID-19 mRNA vaccine, and increased IFN alpha levels were associated with activation of myeloid cells, NK cells, and CD8 T cells. In patients with NSCLC, the COVID mRNA vaccine was associated with an increase in mean TPS of PD-L1. These results support a model in which an LNP mRNA vaccine increases levels of IFN-alpha, systemic myeloid activation and increasing immune activation, including increased expression of PD-L1 on tumor cells. These data support the further development of effective immune stimulants that activate anti-tumor immunity and prime T cells prior to initiating immune checkpoint blockade. Additionally, a randomized clinical trial to validate the effects of COVID mRNA vaccines in patients receiving ICIs is being planned.