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Chordomas are neoplasms derived from notochord cells that typically form in the spine or skull base, and affect both adults and children. Poorly differentiated chordomas, associated with particularly poor outcomes, occur predominantly in children and are characterized by expression of the transcription factor brachyury and loss of INI1/SMARCB1. The use of immune checkpoint inhibitors in pediatric cancer is of growing interest, with reported anti-tumour activity in pediatric Hodgkin lymphoma and gliomas with mismatch repair deficiency. However, responses to immune checkpoint inhibitors are infrequent and unpredictable in pediatric solid tumours, and the molecular markers that can distinguish the seemingly indiscriminate response remain to be defined. Understanding which pediatric patient populations may benefit from immune checkpoint inhibitor therapies is essential. Here we describe the molecular profiles of two pediatric poorly differentiated chordomas using whole-genome, transcriptome and whole-genome bisulfite sequencing as part of the Personalized Oncogenomics program at BC Cancer (NCT02155621) that studies the impact of embedding comprehensive genomic profiling into the clinical care of advanced cancer patients. Genomic profiling and multiplex IHC revealed a high level of CD8+ T cells in both chordoma samples, despite low mutation burden. DNA methylation-based clustering revealed similarities with SMARCB1-deficient rhabdoid tumour subtypes that are have been characterized by increased levels of immune cell infiltration. A dominant tumour-associated T cell receptor clone was identified in one patient sample, which was demonstrated to have affinity for reconstituted brachyury-MHC complexes, indicating a potential anti-tumour immune response directed against brachyury-derived antigens. As these collective observations pointed to a potential benefit of immune targeted therapy, the patient was treated with nivolumab and subsequently achieved a partial radiographic response by RANO criteria. These observations provide support for the benefit of immune checkpoint inhibitors in poorly differentiated chordomas with high levels of infiltrating CD8+ T cells. Citation Format: Laura Williamson, Craig Rive, Daniela Di Francesco, Emma Titmuss, Elizabeth Chun, Scott Brown, Katy Milne, Erin Pleasance, Anna F. Lee, Stephen Yip, David Dix, Daniel Renouf, Robert Holt, Brad H. Nelson, Martin Hirst, Steven Jones, Shahrad Rassekh, Rebecca Deyell, Janessa Laskin, Macro A. Marra. Response to nivolumab in a pediatric chordoma with overexpression of brachyury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 630.

Dramatic and durable responses to immune checkpoint inhibitors (ICIs) have been observed across multiple tumor types, but identifying the patients most likely to respond to these drugs remains challenging, particularly in the context of metastatic and pre-treated disease. Recent clinically approved biomarkers for patient selection are tumor agnostic, but currently all approved markers are evaluated independently. Through the Personalized Onco Genomics (POG) program at BC Cancer, we aimed to study the impact of evaluating multiple biomarkers in a tumor agnostic cohort. We performed whole genome and transcriptome analysis (WGTA) on fresh tumor biopsies from a heterogeneous pan-cancer cohort of 82 patients with advanced metastatic disease subsequently treated with ICIs. Established biomarkers, including tumor mutation burden (TMB) and CD8+ T cell scores, were able to distinguish responders in our advanced and pre-treated cohort. Additionally, we discovered that combining multiple biomarkers provided the best stratification of patients, suggesting a multifaceted approach, such as WGTA, may be suitable for more accurate identification of patients that may benefit from ICIs. As such, we have initiated a Phase II clinical trial, CAPTIV-8 (NCT04273061), which is distinctive in its use of WGTA to evaluate multiple markers including TMB, CD8+ T cell scores, an M1-M2 macrophage score and viral integration to select patients most likely to respond to atezolizumab. Clinical and genomic data prospectively collected from two hundred patients will be evaluated to test the efficacy of combining these biomarkers and identify additional biomarkers of response which can be used to guide treatment with ICIs. Citation Format: Emma Titmuss, Alexandra Pender, Erin Pleasance, Scott Brown, Cameron J. Grisdale, James Topham, Yaoqing Shen, Melika Bonakdar, Gregory A. Taylor, Laura Williamson, Karen Mungall, Eric Chuah, Andrew J. Mungall, Richard A. Moore, Jean-Michel Lavoie, Stephen Yip, Howard Lim, Daniel J. Renouf, Sophie Sun, Steven J. Jones, Robert Holt, Marco A. Marra, Janessa Laskin. CAPTIV-8: A prospective trial of atezolizumab using a multivariate model incorporating whole genome and transcriptome analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1647.

Immunotherapy for patients with non-highly mutated, mismatch repair-proficient (MMRprof) metastatic colorectal cancer has largely been unsuccessful thus far. Here, we used transcriptomics, genomics and in vitro analyses to study the adaptive immune features of colorectal cancer liver metastases (CRLMs), aiming to provide insights into the development of immunotherapies for this common malignancy. Analysis of the RNAseq data from 63 core biopsies obtained in patients enrolled in the Q-CROC-01 trial (NCT00984048) revealed 17 (27%) immune-reactive (IR) CRLMs, defined by concurrent relative high expression of antigen processing, immune cell, immune checkpoint, interferon-gamma response, cytokine, and chemokine transcripts. More T-cell receptor (TCR) sequences were found in IR vs. non-IR CRLMs (mean 89.8 ± 13.3 vs. 19.5 ± 4.0 CDR3 counts, p Our results support that naturally occurring neoAg-reactive T cells may be therapeutically harnessed in a subgroup of metastatic MMRprof colorectal cancer patients selected based on the level of intratumoral immune reactivity, and potentially enhanced by targeting immune checkpoints more biologically relevant than PD-1/PD-L1 and CTLA-4/CD80. Citation Format: Steven Hébert, Mélissa Mathieu, David Henault, Maud Marques, Éric Audemard, Mathieu Courcelles, Scott D. Brown, Pratyaksha Wirapati, Sabine Tejpar, Michael I. D'Angelica, Robert A. Holt, Sylvie Mader, Pierre Thibault, Gerald Batist, Claudia Kleinman, Simon Turcotte. Immune features and neoantigen recognition in mismatch repair-proficient colorectal cancer liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 579.

Immune checkpoint inhibitors are fast becoming a key therapy in the medical oncologist's toolbox across a diverse array of tumour types. The excitement surrounding the utility of these emerging agents is marred by the heterogeneous response observed among patients, highlighting the urgent need for clinically applicable predictive biomarkers. Significant progress has been made in identifying potentially relevant biomarkers including mutation burden and immune infiltration. However, it is still unclear which biomarkers are most predictive across various disease types, and how to integrate various markers of response and resistance for clinical interpretation. We hypothesized that comprehensive genomic profiling, combined with clinical data, would reveal differences in the immuno-oncologic phenotype that could be used as biomarkers for response to checkpoint inhibitor therapy. The Personalized OncoGenomics (POG) study at BC Cancer performs whole genome and transcriptome sequencing of metastatic disease across a diverse array of cancer types to comprehensively characterize cancers and inform clinical therapeutic decision-making. Here we performed in-depth genomic profiling of 64 POG patients who received immune checkpoint inhibitors encompassing multiple disease types including skin, lung, breast, pancreatic and colorectal cancers and sarcomas. Single nucleotide variants, structural variants, copy number alterations, and RNA expression derived from whole genomic and transcriptomic data were used to characterize genomic instability, neoantigen landscape, immune infiltration, and other potential biomarkers of clinical response to checkpoint inhibitors. This collection of putative immune-oncologic biomarkers were integrated into a multivariate model to stratify markers of the tumour immune response. Our analysis shows limited association between PD-L1 expression and checkpoint inhibitor response, consistent with the inadequate effectiveness of this as a universal marker, and shows stronger association between signatures of T cell infiltration based on RNA-Seq data. We also observed patients with low mutation burden that respond to checkpoint inhibitors and show high levels of immune infiltration, and cases with high mutation burden that harbour mechanisms of resistance including reduction in predicted neoantigen diversity. Additional mechanisms of therapeutic resistance observed in post treatment biopsies highlight disruption of antigen presentation and JAK1 mutations in resistant tumours. Our study helps to define which features distinguish patients most likely to respond to checkpoint inhibitors, and uses these features in selecting patients for immunotherapy treatment within the POG clinical trial. Citation Format: Hillary Pearson, Laura Williamson, Erin Pleasance, Scott Brown, Emma Titmuss, Martin Jones, Stuart Zong, Payal Sipahimalani, Yussanne Ma, Steve Jones, Robert Holt, Marco Marra, Janessa Laskin. Integrated whole genome profiling of the immune tumour interaction identifies predictive biomarkers of checkpoint inhibitor response in metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4346.