Immune Therapy Opportunities in Ovarian Cancer

2020 ◽  
pp. e228-e240 ◽  
Author(s):  
Lana E. Kandalaft ◽  
Kunle Odunsi ◽  
George Coukos
Keyword(s):  
Ovarian Cancer ◽  
Immune Therapy ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Small Subset ◽  
T Cell Therapy ◽  
Rational Combination ◽  
Major Direction ◽  
Immune Therapies

Immunotherapy has emerged as a highly promising approach in the treatment of epithelial ovarian cancer (EOC). Immune checkpoint blockade (ICB) therapy, PARP inhibitors (PARPis), neoantigen vaccines, and personalized T-cell therapy have been associated with encouraging clinical activity in a small subset of patients. To increase the proportion of patients who are likely to derive benefit, it will be important not only to generate sufficient numbers of antitumor T cells but also to overcome multiple inhibitory networks in the ovarian tumor microenvironment (TME). Therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies and allow treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies while minimizing toxicities. In this review, we provide progress on immune therapies and future directions for maximally exploiting immune-based strategies for the treatment of ovarian cancer.

scholarly journals Novel therapeutics: response and resistance in ovarian cancer

2019 ◽  
Vol 29 (Suppl 2) ◽  
pp. s16-s21 ◽  
Author(s):  
Dmitriy Zamarin
Keyword(s):  
Ovarian Cancer ◽  
Cancer Research ◽  
Immune Checkpoint ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Blockade ◽  
The Novel ◽  
Novel Therapeutics ◽  
Dna Damaging Agents

Here we review the latest pre-clinical and clinical developments for treatment of ovarian cancer, presented at the American Association of Cancer Research/Rivkin Center Ovarian Cancer Research Symposium held at the University of Washington in September 2018. Abstracts and presentations pertaining to the 'Novel Therapeutics' session were reviewed and are summarized here. The session featured a keynote presentation from Dr Ursula Matulonis, who summarized the current state of the art of treatment of ovarian cancer, including recent clinical trials incorporating the use of novel agents, including poly-ADP-ribose polymerase (PARP) inhibitors, other DNA-damaging agents, vascular endothelial growth factor receptor inhibitors, mirvetuximab soravtansine, and immune checkpoint blockade. Dr Jung-Min Lee then summarized the rationale and the results of early studies for targeting cell cycle checkpoint kinases for anti-cancer therapy. Eight submissions were selected for oral presentations, and 36 abstracts were presented as posters. The topics covered a range of clinical and pre-clinical strategies and biomarkers, including immunotherapy, mechanisms of chemotherapy, and PARP inhibitor resistance, DNA-damaging agents, and other novel therapeutic strategies. Key studies have highlighted that resistance to chemotherapy and PARP inhibitors remain a major challenge in therapy of ovarian cancer. Cancer stem cells represent an important mechanism of chemoresistance and strategies to target these cells may be a pathway to prevention of ovarian cancer relapse. Advancement of novel therapeutics targeting DNA damage, cell metabolism, and endoplasmic reticulum present some of the novel strategies in the pipeline. Emerging compelling pre-clinical data with novel antibody-drug conjugates targeting various surface receptors in ovarian cancer alone and in combination with immune checkpoint blockade generate a strong enthusiasm for rapid translation of these strategies to clinic.

scholarly journals The Role of PARP Inhibitors in the Ovarian Cancer Microenvironment: Moving Forward From Synthetic Lethality

2021 ◽  
Vol 11 ◽  
Author(s):  
Margherita Turinetto ◽  
Giulia Scotto ◽  
Valentina Tuninetti ◽  
Gaia Giannone ◽  
Giorgio Valabrega
Keyword(s):  
Ovarian Cancer ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Synthetic Lethality ◽  
Immune Therapy ◽  
Single Agent ◽  
Parp Inhibitors ◽  
System Response ◽  
Cancer Management ◽  
Target Therapies

PARP inhibitors (PARPi) have shown promising clinical results and have revolutionized the landscape of ovarian cancer management in the last few years. While the core mechanism of action of these drugs has been largely analyzed, the interaction between PARP inhibitors and the microenvironment has been scarcely researched so far. Recent data shows a variety of mechanism through which PARPi might influence the tumor microenvironment and especially the immune system response, that might even partly be the reason behind PARPi efficacy. One of many pathways that are affected is the cGAS-cGAMP-STING; the upregulation of STING (stimulator of interferon genes), produces more Interferon ϒ and pro inflammatory cytokines, thus increasing intratumoral CD4+ and CD8+ T cells. Upregulation of immune checkpoints such as PD1-PDL1 has also been observed. Another interesting mechanism of interaction between PARPi and microenvironment is the ability of PARPi to kill hypoxic cells, as these cells show an intrinsic reduction in the expression and function of the proteins involved in HR. This process has been defined “contextual synthetic lethality”. Despite ovarian cancer having always been considered a poor responder to immune therapy, data is now shedding a new light on the matter. First, OC is much more heterogenous than previously thought, therefore it is fundamental to select predictive biomarkers for target therapies. While single agent therapies have not yielded significant results on the long term, influencing the immune system and the tumor microenvironment via the concomitant use of PARPi and other target therapies might be a more successful approach.

Exploring the true immunotherapy candidates to acquire the promising immunological response in breast carcinomas

2021 ◽  
Author(s):  
Xiang Li ◽  
Lei Ma ◽  
Ye Sun ◽  
Kai Li ◽  
Hong Ren ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Immune Therapy ◽  
Immunological Response ◽  
Immune Checkpoint Blockade ◽  
Cancer Therapies ◽  
Breast Carcinomas ◽  
Immune Effector ◽  
Immune Therapies ◽  
First Time

Abstract Background: Immune checkpoint blockade of immune therapy has been applied in multiple systemic malignancies, and have improved the overall survival to a greater extent, whether it will apply to breast cancer remains unknown. Methods: We endeavored to explore the possible factors that may influence the breast carcinoma associated immune therapy outcomes with using several public databases. Results: The possible treating target of TNF superfamily member 4 (TNFSF4), was selected from massive candidates for its abnormal expression profile, survival associated status, immune system reactions predication. For the first time, we revealed the oncogenic features of TNFSF4 in breast carcinoma, and TNFSF4 was further revealed to be closely related to anti-tumor immunity treatment, including multiple immune effector molecules and T-cell signatures, which was independent on endocrine status, and has not ever been referred to. Moreover, the immune treatment of TNFSF4 blockade also indicated the underling effects on stem cells’ expansion, which more strongly and specifically demonstrated the powerful effects of applying the TNFSF4 blockade based immune therapies in breast carcinomas. Conclusions: For the first time, we aim to dig out the embedding stars that may contribute to breast cancer therapies, and provide one potential but crucial potent for treating breast carcinoma indistinguishably, and long-term effective.

scholarly journals Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Danyang Wang ◽  
Hangyu Zhang ◽  
Tao Xiang ◽  
Gang Wang
Keyword(s):  
Colorectal Cancer ◽  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Adoptive T Cell Therapy ◽  
Therapeutic Approaches ◽  
T Cell Therapy ◽  
Adaptive Immune ◽  
Immune Therapies ◽  
Colorectal Cancer Patients ◽  
Therapeutic Cancer Vaccines

Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the treatment outcomes of immunotherapy in microsatellite-stable (MSS) CRC remain unsatisfactory. As the majority of CRC cases display a molecular MSS/mismatch repair-proficient (pMMR) profile, it is particularly meaningful to explore the clinical applications of adaptive immune therapy in MSS CRC patients. In this review, we summarized the therapeutic approaches of adoptive immune therapies, including cytokines, therapeutic cancer vaccines, adoptive T-cell therapy, and immune checkpoint inhibitors, in the treatment of MSS CRCs.

Evaluation of a RAD51 functional assay in advanced ovarian cancer, a GINECO/GINEGEPS study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5513-5513
Author(s):  
Felix Blanc-Durand ◽  
Elisa Yaniz ◽  
Catherine Genestie ◽  
Etienne Rouleau ◽  
Dominique Berton ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Tumor Cells ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Cycle Phase ◽  
Small Subset ◽  
Functional Assay

5513 Background: Homologous recombination deficiency (HRD), defined as BRCA1/2 mutation ( BRCAmut)or high genomic instability, is currently used to identify patients (pts) with epithelial ovarian cancer (EOC) most likely to benefit from PARP inhibitors. While these genomic tests are useful, they are imperfect: some BRCAm EOC demonstrate primary PARPi resistance and some HR-proficient benefit. Another approach to evaluate HRD is to measure the capacity of tumor cells to recruit nuclear RAD51 foci during S/G2 phase in the presence of double strand DNA damage using multiplexed immunofluorescence (IF) for RAD51, geminin (GMN) and yH2AX. We aimed to describe for the 1st time HRD using this RAD51 functional assay in EOC and correlate RAD51 status to platinum response and BRCAmut. Methods: Tumor samples and clinical data were collected prospectively from pts in the randomized CHIVA trial of neoadjuvant platinum chemotherapy +/- nintedanib. IF for RAD51, GMN, and DAPI was performed on a 3uM slide from FFPE blocks, where feasible, yH2AX was positively scored on a consecutive slide. Tumors were considered RAD51-deficient if < 10% of gem+ tumor cells (TC) had > 5 RAD51+ foci. BRCAmut were identified by NGS. Results: 155 baseline chemotherapy naïve EOC samples were available. All were advanced stage (IIIC/IV), 75% were G3, 7% G2, 2% G1, and 16% grade UK. A contributive RAD51 result was obtained for 90% (139/155) of samples. Contributive NGS results were available for 130 samples. Overall, yH2AX scores were high (median % TC+: 86%, IQR: 56%-100%) confirming the presence of significant basal DNA damage in high grade EOC. Only 8 samples were yH2AX-low, including two of the three G1 tumors. In contrast, 55% (76/155) of samples were considered RAD51-deficient (score < 10%). With regard to outcome, pts with RAD51-deficient tumors had significantly higher overall response rates to neoadjuvant platinum (68% vs 37%, p = 0.04) and significantly longer median progression-free survival (HR 0.50, IC95% 0.25-0.98, p = 0.02). Considering BRCA status, 15% of tumors harbored a deleterious BRCAmut and 67% of these were RAD51-deficient. Importantly among BRCAmut EOC, the RAD51-proficient tumors had significantly poorer response to neoadjuvant chemotherapy (RR = 17% vs 75%, p = 0.02). Conclusions: We evaluated a novel functional assay of HR functionality in advanced EOC. The assay requires minimal tissue and yields contributive results in 90% of cases. Overall, EOC demonstrate high levels of basal DNA damage, yet 55% fail to recruit RAD51 foci during S/G2 cell cycle phase. These RAD51-deficient EOC have improved outcome after neoadjuvant platinum. Conversely, the RAD51 assay also identified a small subset of RAD51-high BRCAmut tumors with poor platinum response. Whether this RAD51 functional assay may also predict PARP inhibitor benefit is currently being investigated.

scholarly journals Immune Therapy for Liver Cancers

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 77 ◽  
Author(s):  
Marc Hilmi ◽  
Angélique Vienot ◽  
Benoît Rousseau ◽  
Cindy Neuzillet
Keyword(s):  
Immune Therapy ◽  
Single Agent ◽  
Survival Rates ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Clinical Activity ◽  
Liver Malignancies ◽  
Liver Cancers ◽  
Advanced Stages ◽  
Infiltrating Lymphocytes

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.

398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A423-A423
Author(s):  
Steven O’Day ◽  
Anthony El khoueiry ◽  
Chethan Ramamurthy ◽  
Andrea Bullock ◽  
Irina Shapiro ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Models ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Control ◽  
Clinical Activity ◽  
Small Subset ◽  
Tumor Bearing Mouse ◽  
High Affinity ◽  
Tumor Bearing

BackgroundImmune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.MethodsThe functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.ResultsPreclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.ConclusionsAGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.Trial RegistrationNCT03860272

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

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