Predictive Gene Signature in MAGE-A3 Antigen-Specific Cancer Immunotherapy

Ulloa‐Montoya, Fernando; Louahed, Jamila; Dizier, Benjamin; Gruselle, Olivier; Spiessens, Bart; Lehmann, Frédéric; Suciu, Stefan; Kruit, Wim; Eggermont, Alexander M.M.; Vansteenkiste, Johan; Brichard, Vincent G.

doi:10.1200/jco.2012.44.3762

Cited by 328 publications

(298 citation statements)

References 34 publications

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“…We then tested the effect of irrelevant peptides spanning the AA sequence of a longer protein, MAGE-A3, a cancer-testis antigen expressed in several tumors including melanoma, lung and bladder cancers, and frequently investigated in cancer vaccine trials. 13 Interestingly, antigen-specific responses measured in the presence of 50, 100, 150, 200, 250 and up to 300 MAGE-A3 peptides were strongly correlated to the responses measured in the absence of MAGE-A3 peptide pools (R > 0.94 and p < 0.0001 for all peptide pools) (Fig. 1E).…”

Section: Resultsmentioning

confidence: 87%

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

et al. 2015

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In immune intervention trials, the comprehensive investigation of immunogenicity or T-cell epitope-mapping is challenging especially when a large set of epitopes needs to be screened and limited sample material is available. To this end, T-cell responses are often monitored using peptide pools. Here, we assessed the magnitude and sensitivity of detection of antigen-specific CD8 C and CD4 C T cells using a single peptide alone or mixed into large pools. Interestingly the magnitude of ex vivo anti-viral and anti-tumor T-cell responses was identical irrespective of the presence and number of irrelevant peptides, in different functional assays with PBMCs from healthy donors and cancer patients. Moreover, the presence of up to 300 irrelevant peptides did not affect the threshold of responsiveness of antigen-specific CD8 C T cells to single cognate peptides. These data demonstrate the relevance of using very large peptide pools for the sensitive and specific immune-monitoring of epitope-specific T cells in natural or immunemodulated context.

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Section: Resultsmentioning

confidence: 87%

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

et al. 2015

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“…Some tumors with low TMB respond completely. Response to immunotherapy has also been associated with intratumoral gene-based markers of T cell activation and antigen presentation 33,34 but such markers have not been introduced to practice. Triple negative breast cancer (TNBC), which comprises the majority of Basal-like tumors, is characterized by relatively high TMB.…”

Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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“…9–11 Recently, Muthuswamy et al reported that intratumoral CD8 T cells in untreated prostate tumors were positively correlated with CXCL9 and CXCL10 levels in the tumor microenvironmen. 12 Consistent with this, we found that CXCL9 and CXCL10 are highly expressed in CD8-infiltrated prostate tumors following sipuleucel-T treatment.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

et al. 2018

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Sipuleucel-T is the only FDA-approved immunotherapy for metastatic castration-resistant prostate cancer. The mechanism by which this treatment improves survival is not fully understood. We have previously shown that this treatment can induce the recruitment of CD4 and CD8 T cells to the tumor microenvironment. In this study, we examined the functional state of these T cells through gene expression profiling. We found that the magnitude of T cell signatures correlated with the frequency of T cells as measured by immunohistochemistry. Sipuleucel-T treatment was associated with increased expression of Th1-associated genes, but not Th2-, Th17 – or Treg-associated genes. Post-treatment tumor tissues with high CD8+T cell infiltration was associated with high levels of CXCL10 expression. On in situ hybridization, CXCL10+ cells colocalized with CD8+T cells in post-treatment prostatectomy tumor tissue. Neoadjuvant sipuleucel-T was also associated with upregulation of immune inhibitory checkpoints, including CTLA4 and TIGIT, and downregulation of the immune activation marker, dipeptidylpeptidase, DPP4. Treatment-associated declines in serum PSA were correlated with induction of Th1 response. In contrast, rises in serum PSA while on treatment were associated with the induction of multiple immune checkpoints, including CTLA4, CEACAM6 and TIGIT. This could represent adaptive immune resistance mechanisms induced by treatment. Taken together, neoadjuvant sipuleucel-T can induce both a Th1 response and negative immune regulation in the prostate cancer microenvironment.

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Predictive Gene Signature in MAGE-A3 Antigen-Specific Cancer Immunotherapy

Abstract: An 84-gene GS associated with clinical response for MAGE-A3 immunotherapeutic was identified in metastatic melanoma and confirmed in resected NSCLC.

Cited by 328 publications

References 34 publications

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

High-throughput monitoring of human tumor-specific T-cell responses with large peptide pools

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Neoadjuvant sipuleucel-T induces both Th1 activation and immune regulation in localized prostate cancer

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