Showing papers by "Fred R. Hirsch published in 2022"

Consensus for HER2 alterations testing in non-small-cell lung cancer

Abstract: Human epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Meanwhile, several HER2-targeted drugs, such as T-DXd, neratinib, afatinib, poziotinib and pyrotinib, have been evaluated in patients with advanced NSCLC, with several of them demonstrating clinical benefit. Therefore, identifying HER2 alterations is pivotal for NSCLC patients to benefit from these targeted therapies. Recent guidelines on HER2 testing were developed for breast and gastric cancer, however, and have not been fully established for NSCLC. The expert group here reached a consensus on HER2 alteration testing in NSCLC with the focus on clinicopathologic characteristics, therapies, detection methods and diagnostic criteria for HER2-altered NSCLC patients. We hope this consensus could improve the clinical management of NSCLC patients with HER2 alterations.

Extracellular vesicle PD-L1 dynamics predict durable response to immune-checkpoint inhibitors and survival in patients with non-small cell lung cancer

Abstract: Abstract Background Immune-checkpoint inhibitors (ICIs) changed the therapeutic landscape of patients with lung cancer. However, only a subset of them derived clinical benefit and evidenced the need to identify reliable predictive biomarkers. Liquid biopsy is the non-invasive and repeatable analysis of biological material in body fluids and a promising tool for cancer biomarkers discovery. In particular, there is growing evidence that extracellular vesicles (EVs) play an important role in tumor progression and in tumor-immune interactions. Thus, we evaluated whether extracellular vesicle PD-L1 expression could be used as a biomarker for prediction of durable treatment response and survival in patients with non-small cell lung cancer (NSCLC) undergoing treatment with ICIs. Methods Dynamic changes in EV PD-L1 were analyzed in plasma samples collected before and at 9 ± 1 weeks during treatment in a retrospective and a prospective independent cohorts of 33 and 39 patients, respectively. Results As a result, an increase in EV PD-L1 was observed in non-responders in comparison to responders and was an independent biomarker for shorter progression-free survival and overall survival. To the contrary, tissue PD-L1 expression, the commonly used biomarker, was not predictive neither for durable response nor survival. Conclusion These findings indicate that EV PD-L1 dynamics could be used to stratify patients with advanced NSCLC who would experience durable benefit from ICIs.

Expression patterns and prognostic relevance of subtype‐specific transcription factors in surgically resected small‐cell lung cancer: an international multicenter study

Abstract: The tissue distribution and prognostic relevance of subtype‐specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small‐cell lung cancer (SCLC). The expression of subtype‐specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype‐specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC‐A (ASCL1‐dominant), SCLC‐AN (combined ASCL1/NEUROD1), SCLC‐N (NEUROD1‐dominant), and SCLC‐P (POU2F3‐dominant), IHC and cluster analyses identified a quadruple‐negative SCLC subtype (SCLC‐QN). No unique YAP1‐subtype was found. The highest overall survival rates were associated with non‐neuroendocrine subtypes (SCLC‐P and SCLC‐QN) and the lowest with neuroendocrine subtypes (SCLC‐A, SCLC‐N, SCLC‐AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard‐of‐care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype‐specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1‐subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma

Abstract: Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)— either as monotherapy or in combination with other ICIs or chemotherapy—have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC’s 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.

Circulating tumor DNA (ctDNA) kinetics predict progression-free and overall survival in EGFR TKI-treated patients with EGFR-mutant NSCLC (SWOG S1403).

Abstract: PURPOSE Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome. EXPERIMENTAL DESIGN Serial plasma ctDNA (baseline, 8 weeks and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib +/- cetuximab in TKI-naive, EGFR-mutation tissue-positive NSCLC. RESULTS EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR-mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared to those with persistent ctDNA at C3D1 (HR (95% CI): 0.23 (0.12-0.45), p<0.0001); with a median PFS of 15.1 (95% CI: 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR (95% CI): 0.44 (0.21-0.90), p=0.02; mOS: 32.6 versus 15.6 (4.9-28.3) months. CONCLUSIONS Plasma clearance of mutant EGFR ctDNA at 8-weeks was highly and significantly predictive of progression-free and overall survival, outperforming RECIST response for predicting long-term benefit.

The Armed Conflict and the Impact on Patients With Cancer in Ukraine: Urgent Considerations

Abstract: On February 24, 2022, a war began within the Ukrainian borders. At least 3.0 million Ukrainian inhabitants have already fled the country. Critical infrastructure, including hospitals, has been damaged. Children with cancer were urgently transported to foreign countries, in an effort to minimize interruption of their life-saving treatments. Most adults did not have that option. War breeds cancer—delaying diagnosis, preventing treatment, and increasing risk. We project that a modest delay in care of only 4 months for five prevalent types of cancer will lead to an excess of over 3,600 cancer deaths in the subsequent years. It is critical that we establish plans to mitigate that risk as soon as possible.

Coronavirus Disease 2019 Outcomes, Patient Vaccination Status, and Cancer-Related Delays During the Omicron Wave: A Brief Report From the TERAVOLT Analysis

Abstract: IntroductionThe Thoracic Centers International coronavirus disease 2019 (COVID-19) Collaboration (TERAVOLT) registry found approximately 30% mortality in patients with thoracic malignancies during the initial COVID-19 surges. Data from South Africa suggested a decrease in severity and mortality with the Omicron wave. Our objective was to assess mortality of patients with thoracic malignancies with the Omicron-predominant wave and evaluate efficacy of vaccination.MethodsA prospective, multicenter observational study was conducted. A total of 28 institutions contributed data from January 14, 2022, to February 4, 2022. Inclusion criteria were any thoracic cancer and a COVID-19 diagnosis on or after November 1, 2021. End points included mortality, hospitalization, symptomatic COVID-19 infection, asymptomatic COVID-19 infection, and delay in cancer therapy. Analysis was done through contingency tables and a multivariable logistic model.ResultsWe enrolled a total of 346 patients. Median age was 65 years, 52.3% were female, 74.2% were current or former smokers, 86% had NSCLC, 72% had stage IV at time of COVID-19 diagnosis, and 66% were receiving cancer therapy. Variant was unknown for 70%; for those known, Omicron represented 82%. Overall mortality was 3.2%. Using multivariate analysis, COVID-19 vaccination with booster compared with no vaccination had a protective effect on hospitalization or death (OR = 0.30, confidence interval: 0.15–0.57, p = 0.0003), whereas vaccination without booster did not (OR = 0.64, confidence interval: 0.33–1.24, p = 0.1864). Cancer care was delayed in 56.4% of the patients.ConclusionsTERAVOLT found reduced patient mortality with the most recent COVID-19 surge. COVID-19 vaccination with booster improved outcomes of hospitalization or death. Delays in cancer therapy remain an issue, which has the potential to worsen cancer-related mortality.

Loss of STING expression is prognostic in non–small cell lung cancer

Abstract: Stimulator of interferon (IFN) genes (STING) is a protein that promotes type I IFN production essential for T‐cell activation. In this study, we aim to characterize STING expression comprehensively using The Cancer Genome Atlas (TCGA) database, cell lines, and patient tumor samples stained with immunohistochemistry.

Baseline extracellular vesicle TGF‐β is a predictive biomarker for response to immune checkpoint inhibitors and survival in non–small cell lung cancer

Abstract: Immune‐checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD‐L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor‐β (TGF‐β), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF‐β is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF‐β in patients with non–small‐cell lung cancer receiving ICIs.

Supporting Patients with Cancer after Dobbs v. Jackson Women’s Health Organization

Abstract: In the context of cancer, whether or not to choose pregnancy termination represents a difficult and multifaceted decision. In this editorial, members of The Oncologist editorial team attempt to contextualize the potential implications of the recent Supreme Court decision in Dobbs v. Jackson Women’s Health Organizationfor patients with cancer.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies

Abstract: Abstract Background Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation’s largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Predictive Biomarkers for Immunotherapy in Lung Cancer: Perspective From the International Association for the Study of Lung Cancer Pathology Committee

Abstract: Immunotherapy including immune checkpoint inhibitors (ICIs) has become the backbone of treatment for most lung cancers with advanced or metastatic disease. In addition, they have increasingly been used for early stage tumors in neoadjuvant and adjuvant settings. Unfortunately, however, only a subset of patients experiences meaningful response to ICIs. Although programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry (IHC) has played a role as the principal predictive biomarker for immunotherapy, its performance may not be optimal, and it suffers multiple practical issues with different companion diagnostic assays approved. Similarly, tumor mutational burden (TMB) has multiple technical issues as a predictive biomarker for ICIs. Now, ongoing research on tumorand host immune-specific factors has identified immunotherapy biomarkers that may provide better response and prognosis prediction, in particular in a multimodal approach. This review by the International Association for the Study of Lung Cancer Pathology Committee provides an overview of various immunotherapy biomarkers, including updated data on PD-L1 IHC and TMB, and assessments of neoantigens, genetic and epigenetic signatures, immune microenvironment by IHC and transcriptomics, and microbiome and pathologic response to neoadjuvant immunotherapies. The aim of this review is to underline the efficacy of new individual or combined predictive biomarkers beyond PD-L1 IHC and TMB. 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Real‐World longitudinal practice patterns in the use of PD‐1 and PD‐L1 inhibitors as First‐Line therapy in patients with Non‐Small cell lung cancer in the United States

Abstract: Immune checkpoint inhibitors targeting the programmed cell death protein‐1 (PD‐1) and programmed death ligand‐1 (PD‐L1) axis (collectively referred to as PD[L]1i) have demonstrated clinical benefits in non‐small cell lung cancer (NSCLC) patients. The purpose of this United States‐based real‐world study is to examine changes in the landscape of first‐line therapies for NSCLC since the introduction of PD(L)1i.

A phase 1b/2 trial of dupilumab given in conjunction with PD-(L)1 blockade in the treatment of relapsed/refractory metastatic NSCLC.

Abstract: TPS9139 Background: Although tumor microenvironments may contain chronic inflammatory cells, this milieu can lead to immune evasion and may contribute to resistance to immunotherapy. Dendritic cells are one of the most potent cross presenters of tumor antigen, and their function is crucial to tumor-directed adaptive immune responses. In the KP mouse model of lung adenocarcinoma (KrasG12D; Tp53-/-), we recently identified interleukin-4 (IL-4)-driven suppression of tumor-antigen charged dendritic cells, which was similarly seen in human lung cancer lesions (Maier, B., et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature, 2020.580[7802]:257-262). In the mouse model IL-4 blockade resulted in an increase in IL-12, IFNg and TNF in CD8+ T cells and decreased tumor burden, and further antitumor activity was seen when combined with PD-L1 blockade. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit which disrupts signaling through receptors for both IL-4 and IL-13; it is FDA approved for patients with multiple atopic conditions, in whom series adverse effects are rare. Based on this pre-clinical data, we hypothesize that the addition of dupilumab to anti PD-(L)1 therapy will be well tolerated, and will rescue the anti-tumor effect of immune checkpoint blockade. Methods: This is a phase Ib/II trial. Patients with relapsed/refractory NSCLC who have received prior anti PD-(L)1 treatment are eligible for enrollment. In a phase Ib safety run-in, six patients will be enrolled in a modified set-dose 3+3 design. If no more than 1 DLT is observed during this phase, the trial will proceed to phase II. Phase II will enroll a further 15 patients in a minimax design with early stopping for futility to a maximum total of 21 patients. Patients will undergo pre-treatment biopsies and peripheral blood sampling prior to receiving 3 doses of dupilumab, administered every three weeks, in conjunction with continuing standard-of-care anti-PD-(L)1 therapy. Patients will undergo repeat biopsies 4 weeks after starting therapy. After completion of dupilumab (at 9 weeks) patients will undergo repeat staging. The primary endpoint of phase 1b is safety as measured by frequency and severity of adverse effects. The primary endpoint of phase II is overall response rate as assessed using RECIST 1.1 criteria at the time of post-dupilumab imaging. Exploratory endpoints include analysis of peripheral blood by CyTOF and O-link, and tissue biopsies will be analyzed by multiplex-IHC and bulk-RNA-sequencing. T cell receptor sequencing will be performed on tumor and matched peripheral blood samples, and circulating tumor DNA will be assessed at multiple time points. Phase 1b is currently enrolling as planned. Clinical trial information: NCT05013450.

Corrigendum to 'Consensus for HER2 Alterations Testing in Non-small Cell Lung Cancer': [ESMO Open Volume 7 Issue 1 (2022) 100395].

Abstract: The authors regret the Author Affiliations of Dr. Jianming Ying and Dr. Ying Cheng were listed incorrectly in the published paper. The correct affiliations are as follows: Jianming Ying, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Ying Cheng, Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China. All other author affiliations are correct. The authors would like to apologise for any inconvenience caused. Consensus for HER2 alterations testing in non-small-cell lung cancerESMO OpenVol. 7Issue 1PreviewHuman epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Full-Text PDF Open Access

29 Lung-MAP composite signature for immune checkpoint inhibitor (ICI) efficacy in advanced squamous cell lung cancer (SCC)

Abstract:

Background

Predictive biomarkers for ICI regimens in NSCLC, namely PD-L1 and tumor mutational burden (TMB), remain suboptimal, leaving oncologists with limited decision-making tools. We sought to develop a more comprehensive solution, integrating genomic alterations detected by comprehensive genomic profiling (CGP), to enrich for association with progression-free survival (PFS) and overall survival (OS).

Methods

Lung Master Protocol (Lung-MAP) is an NCI-sponsored public-private partnership evaluating new therapies for previously-treated advanced stage NSCLC. In this analysis, 320 SCC patients from sub-studies S1400A (n=68; durvalumab) and S1400I (n=252; nivolumab ± ipilimumab) had tissue CGP data by Foundation Medicine. 204 patients from S1400A (n=43; SP263) and S1400I (n=161; 28–8 pharmDX) had PD-L1 IHC. We evaluated TMB (0–9, 10–20, >20 mut/Mb), PD-L1 IHC, HLA loss of heterozygosity (LOH) of ≥ 1 gene (evaluable for n=206), mutations in KEAP1/NFE2L2, DNA damage response genes,ARID1A, and loss of CDKN2A as potential ICI biomarkers. Wilcoxon and Fisher’s exact tests assessed association between continuous TMB/PDL1 IHC (<1%, 1–49%, ≥50%) and each binary biomarker, and between pairs of binary markers. Cox proportional hazards model evaluated the association between each biomarker and OS/PFS, adjusting for age, sex, smoking status, and stage. Based on significance (at the nominal 0.1 level without correction for multiplicity) from univariate analysis, multiple combination signatures were analyzed using a predetermined scoring system. Biomarkers in the most significant combination signature was further examined by adjusting for TMB and PD-L1, to demonstrate if they provided additional value.

Results

Despite associations between TMB and ARID1A mutations (P = 0.009), PD-L1and KEAP1/NFE2L2 mutations (P = 0.007) and ARID1A mutations and KEAP1/NFE2L2 mutations (OR = 2.89; 95% CI, 1.43 – 5.91, P = 0.0016), the magnitude of correlation was modest, thus representing complementary predictors. Higher TMB (>20 vs. 10–20 vs. 0–9) was the most significant positive predictor of OS (HR=0.79; 95% CI, 0.65–0.95, p=0.01). A composite combinatorial signature (ICIsig) inclusive of TMB, PD-L1, HLA LOH, ARID1A, and KEAP1/NFE2L2 mutations was associated with better OS (HR=0.76; 95% CI, 0.63–0.92, p=0.005) and PFS (HR=0.84; 95% CI, 0.70–0.99, p=0.048). Landmark 3-year OS rates were 29% vs. 6% in ICIsig high vs. low. ICIsig high represented 39% of the evaluable population.

Conclusions

We show that a composite ICIsig extending beyond TMB and PD-L1 captures NSCLC patients benefiting from ICI therapy more effectively than single biomarkers. ICIsig could inform treatment selection in today’s rapidly expanding therapeutic landscape. Validation from a large randomized Phase III trial is ongoing.

Acknowledgements

We would like to acknowledge funding from: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and by AstraZeneca and Bristol-Myers Squibb Company, through the Foundation for the National Institutes of Health, in partnership with Friends of Cancer Research.

Abstract CT205: A phase I/Ib trial of intratumoral Poly-ICLC in resectable malignant pleural mesothelioma

Abstract: Background: Malignant pleural mesothelioma (MPM) is usually fatal, though multimodality therapy— now including immunotherapy— has improved survival. Recurrence after surgery is close to 100%, even with adjuvant chemotherapy and radiation. Our collaborators have performed deep immunophenotyping of treatment-naïve MPM lesions using mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq) to define the tumor microenvironment. A population of rare CD141+ dendritic cells (DC1) is disproportionately represented in some MPM lesions analyzed. These DC1 cells— which express high levels of Toll-like receptor 3 (TLR3)— are among the most potent cross-presenters of antigen and are key to priming anti-tumor CD4+ and CD8+ T cell responses. Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC), is a double-stranded RNA host-targeted therapeutic viral-mimic. Poly-ICLC activates multiple innate immune receptors including TLR3 and melanoma differentiation-associated gene 5 (MDA5), leading to cross-presentation of antigen to T cells and induction of strong Th1 response. We hypothesize that injection of poly-ICLC prior to surgical resection may activate intratumoral (IT) DC1s, increase tumor antigen presentation to cytotoxic T cells, and induce tumor-specific immune surveillance. Methods: This is a phase I/Ib study to evaluate the safety of IT poly-ICLC prior to surgical resection for patients with MPM (NCT04525859). The primary endpoint is safety as assessed by frequency and severity of toxicities by CTCAE 5.0. Secondary endpoints are objective response as measured by RECIST 1.1 and recurrence free survival measured from the time of first poly-ICLC injection. Exploratory endpoints include evaluation of circulating immune cells (including regulatory T cells and NK cells), evaluation of immune cell infiltration in pre-injection tumor biopsy and surgically resected tissue, as well as characterization of immune parameters such as local B cell specificity. The protocol features a Simon’s two-stage design, with six patients enrolled in a phase I safety cohort, proceeding to a phase Ib expansion cohort (additional 13 patients) if no more than 1 dose limiting toxicity occurs. Eligible patients must have MPM deemed operable by the treating thoracic surgeon. Eligible subjects may not have uncontrolled immunocompromised states or autoimmune disorders. After enrollment, patients undergo biopsies at which time 2mg poly-ICLC is injected across two sites in the tumor. Patients then undergo resection of the tumor (pleurectomy/decortication or extra pleural pneumonectomy per standard of care) at day 21+/- 7 after poly-ICLC injection. Blood is drawn at three points (prior to poly-ICLC injection, at time of surgery, and at a post-operative visit) for immune profiling. At the time of submission six patients have been treated and phase Ib accrual is continuing as planned. Interim analysis of phase I safety and exploratory endpoints will be reported in late 2022. Citation Format: Bailey G. Fitzgerald, Thomas U. Marron, Robert Sweeney, Jorge Gomez, Nicole Hall, Daniel O'Grady, Christian Rolfo, Raj Veluswamy, Deborah Doroshow, John Mandeli, David Yankelevitz, Nina Bhardwaj, Sacha Gnjatic, Fred R. Hirsch, Miriam Merad, Alexander Tsankov, Raja Flores, Andrea Wolf. A phase I/Ib trial of intratumoral Poly-ICLC in resectable malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT205.