Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

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Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer (NSCLC) patients with EGFR or HER2 exon 20 insertions.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21540 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21540-e21540 ◽

Cited By ~ 1

Author(s):

Kaiyan Chen ◽

Guoqiang Pan ◽

Yanjun Xu ◽

Yun Fan

Keyword(s):

Tumor Infiltrating Lymphocytes ◽

Small Cell Lung ◽

Immune Microenvironment ◽

Limited Efficacy ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Exon 20 ◽

Nsclc Patients ◽

L1 Protein ◽

Infiltrating Lymphocytes

e21540 Background: This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with insertions in exon 20 (Ex20ins) of EGFR or HER2. Methods: Molecular spectrum, tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) were reviewed for NSCLC patients with Ex20ins of EGFR or HER2. Results: Thirty-five patients carrying EGFR Ex20ins and 21 patients harboring HER2 Ex20ins were retrospectively enrolled between April 2016 and September 2018. The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than those with HER2 mutations (48.6% vs. 19.0%, P=0.027). High TMB and PD-L1 expression was independently associated with considerably poor prognosis (P=0.025, P=0.045; respectively). Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins. Conclusions: NSCLC patients with EGFR/ HER2 Ex20ins had distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the underlying reason for the different responses to PD-1/PD-L1 blockage.

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The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

10.21203/rs.3.rs-25670/v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Diego Salas-Benito ◽

Enrique Conde ◽

Ibon Tamayo-Uria ◽

Uxua Mancheño ◽

Edurne Elizalde ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

T Cell ◽

Predictive Biomarkers ◽

Tumor Infiltrating Lymphocytes ◽

Ovarian Tumors ◽

Autologous Tumor ◽

Tumor Mutational Burden ◽

Nanostring Technology ◽

Infiltrating Lymphocytes

Abstract Background: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as programmed cell death protein 1 (PD-1), for tumor-specific T-cell enrichment, as well as predictive biomarkers that help identify those patients capable of rendering tumor-reactive TIL products. We have investigated this in ovarian cancer (OC) patients as candidate for TIL therapy implementation. Methods: PD-1- and PD-1+ CD8 TILs were isolated from resected ovarian tumors and, after polyclonal expansion, TIL products were tested against autologous tumor cells. Reactivity was assessed by IFNg production (ELISPOT) and upregulation of CD137. Baseline tumor samples were examined using flow cytometry, multiplexed quantitative immunofluorescence, Nanostring technology, for gene expression profile (GEP) analyses, as well as a next generation sequencing gene panel, for tumor mutational burden (TMB) calculation, to identify those features that distinguished patients with tumor-reactive and non-tumor-reactive TIL products.Results: Tumor-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Flow-cytometric studies revealed that fresh tumors from patients rendering tumor-reactive TILs presented a significantly higher frequency of CD137+ cells within the PD1+CD8+ subset. Multiplexed immunofluorescence supported this finding, which was particularly striking in intraepithelial CD8 TILs. Baseline GEP analysis showed that patients rendering tumor-reactive TILs exhibited a significantly higher T-cell inflamed signature. Despite no correlation between TMB and GEP, both parameters stratified tumors, with patients with higher TMB and/or T-cell inflamed signature score rendering tumor-reactive TILs. Conclusion: We have demonstrated that PD-1 identifies autologous-tumor specific CD8 T cells infiltrating ovarian tumors and have uncovered predictive factors that identify OC patients who are likely to render tumor-reactive cells from PD-1+ TILs. These findings have important implications for improving the efficacy of TIL therapy in OC.

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Tumor-Infiltrating Lymphocytes, Tumor Mutational Burden, and Genetic Alterations in Microsatellite Unstable, Microsatellite Stable, or Mutant POLE/POLD1 Colon Cancer

JCO Precision Oncology ◽

10.1200/po.20.00456 ◽

2021 ◽

pp. 817-826

Author(s):

Ajaratu Keshinro ◽

Chad Vanderbilt ◽

Jin K. Kim ◽

Canan Firat ◽

Chin-Tung Chen ◽

...

Keyword(s):

Colon Cancer ◽

Structural Changes ◽

Transforming Growth Factor ◽

Tumor Infiltrating Lymphocytes ◽

Genetic Alterations ◽

High Power Field ◽

Colon Tumors ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Infiltrating Lymphocytes

PURPOSE To characterize the relationship between tumor-infiltrating lymphocytes (TIL), tumor mutational burden (TMB), and genetic alterations in microsatellite stable (MSS), microsatellite instability (MSI), or mutant POLE/POLD1 colon cancer. MATERIALS AND METHODS Four hundred ninety-nine resected stage I-III colon tumors treated between 2014 and 2019 were assessed for TIL; somatic mutations, copy number alterations, and structural changes in > 400 oncogenes; and MSI status. RESULTS Of the 499 tumors analyzed, 313 were MSS, 175 were MSI, and 11 had POLE/POLD1 pathogenic mutations. Both the percentage of tumors with a high level of TIL (≥ 4 lymphocytes per high-power field) and the median TMB differed significantly between the three phenotypes: MSS, 4.5% and 6 mutations/Mb; MSI, 68% and 54 mutations/Mb; POLE/POLD1, 82% and 158 mutations/Mb ( P < .05). Within each phenotype, TMB did not vary significantly with TIL level. Among MSI tumors, the median number of frameshift indels was significantly higher in tumors with high levels of TIL (20 v 17; P = .018). In the MSS group, significantly higher proportions of tumors with high levels of TIL had mutations in the transforming growth factor-β (36% v 12%; P = .01), RAS (86% v 54%; P = .02), and Hippo (7% v 1%; P = .046) pathways; in contrast, TP53 alterations were associated with low levels of TIL (74% v 43%; P = .01). CONCLUSION The association between TIL, TMB, and genetic alterations varies significantly between MSI, MSS, and mutant POLE/POLD1 colon tumors. These differences may help explain tumoral immunity and lead to predictors of response to immunotherapy.

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Metaplastic breast cancers: Genomic profiling, mutational burden and tumor-infiltrating lymphocytes

The Breast ◽

10.1016/j.breast.2018.12.010 ◽

2019 ◽

Vol 44 ◽

pp. 29-32 ◽

Cited By ~ 8

Author(s):

Nancy Tray ◽

Jessica Taff ◽

Baljit Singh ◽

James Suh ◽

Nhu Ngo ◽

...

Keyword(s):

Tumor Infiltrating Lymphocytes ◽

Genomic Profiling ◽

Breast Cancers ◽

Mutational Burden ◽

Infiltrating Lymphocytes

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Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

JAMA Oncology ◽

10.1001/jamaoncol.2017.3290 ◽

2017 ◽

Vol 3 (12) ◽

pp. e173290 ◽

Cited By ~ 90

Author(s):

◽

Ellen L. Goode ◽

Matthew S. Block ◽

Kimberly R. Kalli ◽

Robert A. Vierkant ◽

...

Keyword(s):

Ovarian Cancer ◽

Survival Time ◽

Dose Response ◽

Tumor Infiltrating Lymphocytes ◽

High Grade ◽

Serous Ovarian Cancer ◽

Infiltrating Lymphocytes

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Nomograms to Predict the Density of Tumor-Infiltrating Lymphocytes in Patients With High-Grade Serous Ovarian Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.590414 ◽

2021 ◽

Vol 11 ◽

Author(s):

Danian Dai ◽

Lili Liu ◽

He Huang ◽

Shangqiu Chen ◽

Bo Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

Menopausal Status ◽

Tumor Infiltrating Lymphocytes ◽

Roc Curves ◽

Clinicopathological Characteristics ◽

High Grade ◽

Serous Ovarian Cancer ◽

Ki 67 ◽

Infiltrating Lymphocytes

BackgroundTumor-infiltrating lymphocytes (TILs) have important roles in predicting tumor therapeutic responses and progression, however, the method of evaluating TILs is complicated. We attempted to explore the association of TILs with clinicopathological characteristics and blood indicators, and to develop nomograms to predict the density of TILs in patients with high-grade serous ovarian cancer (HGSOC).MethodsThe clinical profiles of 197 consecutive postoperative HGSOC patients were retrospectively analyzed. Tumor tissues and matched normal fallopian tubes were immunostained for CD3+, CD8+, and CD4+ T cells on corresponding tissue microarrays and the numbers of TILs were counted using the NIH ImageJ software. The patients were classified into low- or high-density groups for each marker (CD3, CD4, CD8). The associations of the investigated TILs to clinicopathological characteristics and blood indicators were assessed and the related predictors for densities of TILs were used to develop nomograms; which were then further evaluated using the C-index, receiver operating characteristic (ROC) curves and calibration plots.ResultsMenopausal status, estrogen receptor (ER), Ki-67 index, white blood cell (WBC), platelets (PLT), lactate dehydrogenase (LDH), and carbohydrate antigen 153 (CA153) had significant association with densities of tumor-infiltrating CD3+, CD8+, or CD4+ T cells. The calibration curves of the CD3+ (C-index = 0.748), CD8+ (C-index = 0.683) and CD4+ TILs nomogram (C-index = 0.759) demonstrated excellent agreement between predictions and actual observations. ROC curves of internal validation indicated good discrimination for the CD8+ TILs nomogram [area under the curve (AUC) = 0.659, 95% CI 0.582–0.736] and encouraging performance for the CD3+ (AUC= 0.708, 95% CI 0.636–0.781) and CD4+ TILs nomogram (AUC = 0.730, 95% CI 0.659–0.801).ConclusionMenopausal status, ER, Ki-67 index, WBC, PLT, LDH, and CA153 could reflect the densities of T cells in the tumor microenvironment. Novel nomograms are conducive to monitor the immune status of patients with HGSOC and help doctors to formulate the appropriate treatment strategies.

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The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Cancers ◽

10.3390/cancers10080242 ◽

2018 ◽

Vol 10 (8) ◽

pp. 242 ◽

Cited By ~ 37

Author(s):

Galaxia Rodriguez ◽

Kristianne Galpin ◽

Curtis McCloskey ◽

Barbara Vanderhyden

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Epithelial Ovarian Cancer ◽

B Lymphocytes ◽

Immune Cells ◽

Ovarian Cancer Cell ◽

Cell Types ◽

Therapeutic Approaches ◽

Mutational Burden ◽

Tumor Mutational Burden

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

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Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study

OncoImmunology ◽

10.1080/2162402x.2018.1502905 ◽

2018 ◽

Vol 7 (12) ◽

pp. e1502905 ◽

Cited By ~ 22

Author(s):

Magnus Pedersen ◽

Marie Christine Wulff Westergaard ◽

Katy Milne ◽

Morten Nielsen ◽

Troels Holz Borch ◽

...

Keyword(s):

Ovarian Cancer ◽

Pilot Study ◽

Cell Therapy ◽

Adoptive Cell Therapy ◽

Tumor Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

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Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8+ T Cells in Non-Melanoma Cancers Compared to Melanoma

Cancers ◽

10.3390/cancers12113344 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3344

Author(s):

Aishwarya Gokuldass ◽

Arianna Draghi ◽

Krisztian Papp ◽

Troels Holz Borch ◽

Morten Nielsen ◽

...

Keyword(s):

Ovarian Cancer ◽

T Cells ◽

T Cell ◽

Tumor Infiltrating Lymphocytes ◽

Autologous Tumor ◽

Epithelial Cancers ◽

Single Cell Rna Sequencing ◽

Tumor Types ◽

Infiltrating Lymphocytes

Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

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