Unmet needs in cervical cancer - can biological therapies plug the gap?

INTRODUCTION: Cervical cancer remains one of the most common gynecologic malignancies worldwide. A disproportionate burden of cases occurs in developing countries due to inadequate screening and treatment. Even among patients adequately treated, in the presence of locally advanced or recurrent disease, outcomes tend to be poor. The introduction of biologic therapy into treatment has increased overall survival; however, a considerable opportunity still exists to improve current standards in treatment. Biologics have shown antitumor activity in multiple tumor types and are actively being pursued for the management of cervical cancer. AREAS COVERED: In this article, we will discuss the historical evolution of biologic therapy in cervical cancer including use of angiogenesis inhibitors, immune checkpoint inhibitors, antibody-drug conjugates, and vaccines. We will review how these therapies have been integrated into current treatment recommendations and discuss ongoing investigations intended to improve clinical outcomes. We also postulate on persistent gaps in care. EXPERT OPINION: Biologic therapies have had a tremendous impact on our current approach to managing cervical cancer. We anticipate that significant more research and development will be committed to the continued investigation of biologics in cervical cancer in an effort to improve a historically difficult to treat malignancy.

Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.

BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer.

Background: Treatment of recurrent platinum-resistant high grade serous ovarian cancer (HGSOC) remains a challenge. Novel treatment options for recurrent disease are an unmet need. Case: A 69-year-old with recurrent, metastatic, platinum-resistant HGSOC overexpressing TROP2 experienced a significant response to the antibody-drug conjugate (ADC) sacituzumab govitecan after multiple failed lines of chemotherapy and targeted treatment. Following sacituzumab govitecan treatment she experienced a confirmed partial response as well as a return of CA-125 to baseline. Having now completed 8 cycles (ie, over 6 months of treatment), her disease continues to demonstrate a response to sacituzumab govitecan treatment. The ADC has been well tolerated at a dose of 10 mg/kg with no dose-limiting toxicity or need for dose reductions. Conclusion: Sacituzumab govitecan may represent a treatment option for platinum-resistant/recurrent HGSOC that have previously failed prior lines of chemotherapy. Clinical trials with sacituzumab govitecan in platinum-resistant ovarian cancer patients are currently ongoing (https://classic.clinicaltrials.gov/ct2/show/NCT06028932).

Preclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma.

INTRODUCTION: Epithelial ovarian cancer (EOC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical activity of datopotamab deruxtecan (Dato-Dxd), a novel TROP2 targeting antibody drug conjugate (ADC) in ovarian cancer cell lines and xenografts with variable TROP2 expression. METHODS: In vitro cell viability with Dato-DXd was assessed using flow-cytometry based assays against a panel of EOC primary cell lines with variable TROP2 expression. Fluorescent anti-phospho-histone H2A.X antibody was used to detect dsDNA breaks by flow-cytometry. The in vivo antitumor activity of Dato-DXd was tested in TROP2 overexpressing xenografts. RESULTS: TROP2 overexpressing (3+) and moderate (2+) expressing EOC cell lines demonstrated higher sensitivity to Dato-DXd when compared to TROP2 negative tumors. Dato-DXd exposed TROP2+ EOC demonstrated increased dsDNA breaks and Annexin-V positivity (a marker of apoptosis) when compared to tumor cells exposed to the non-binding conjugate (p = 0.001 and p = 0.016, respectively). Dato-DXd induced significant antibody-dependent cellular cytotoxicity (ADCC) in the presence of peripheral-blood-lymphocytes. While negligible activity was detected against EOC cell lines with low TROP2 expression, Dato-DXd demonstrated significant bystander killing against tumor cells with low/negligible TROP2 when such cells were admixed with TROP2 3+ tumor cells in vitro. Dato-DXd showed tumor growth suppression against EOC cell line derived xenograft models that overexpress TROP2 at 3+ levels, prolonging survival when compared to controls, with minimal toxicity. CONCLUSION: Dato-DXd shows promising preclinical activity against TROP2 overexpressing ovarian cancers. Future clinical trials in ovarian cancer patients are warranted.

Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer.

PURPOSE: Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)-directed antibody-drug conjugate, in patients with advanced EC. METHODS: TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. RESULTS: At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. CONCLUSION: Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.

Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2.

High-grade serous ovarian cancer (HGSOC) and ovarian clear cell carcinoma (CC), are biologically aggressive tumors endowed with the ability to rapidly metastasize to the abdominal cavity and distant organs. About 10% of HGSOC and 30% of CC demonstrate HER2 IHC 3 + receptor over-expression. We evaluated the efficacy of trastuzumab deruxtecan (T-DXd; DS-8201a), a novel HER2-targeting antibody-drug conjugate (ADC) to an ADC isotype control (CTL ADC) against multiple HGSOC and CC tumor models. Eleven ovarian cancer cell lines including a matched primary and metastatic cell line established from the same patient, were evaluated for HER2 expression by immunohistochemistry and flow cytometry, and gene amplification by fluorescence in situ hybridization assays. In vitro experiments demonstrated T-DXd to be significantly more effective against HER2 3 + HGSOC and CC cell lines when compared to CTL ADC (p < 0.0001). T-DXd induced efficient bystander killing of HER2 non-expressing tumor cells when admixed with HER2 3 + cells. In vivo activity of T-DXd was studied in HER2 IHC 3 + HGSOC and CC mouse xenograft models. We found T-DXd to be significantly more effective than CTL ADC against HER2 3 + HGSOC (KR(CH)31) and CC (OVA10) xenografts with a significant difference in tumor growth starting at day 8 (p = 0.0003 for KR(CH)31, p < 0.0001 for OVA10). T-DXd also conferred a survival advantage in both xenograft models. T-DXd may represent an effective ADC against primary and metastatic HER2-overexpressing HGSOC and CC.

Targetable ERBB2/HER2 Mutations in Gynecologic Malignancies: Clinicopathological, Immunohistochemical, and Molecular Correlations.

Targeted anti-HER2 therapy has been recently added to the standard treatment recommendations in endometrial serous carcinoma. Current eligibility requires testing for HER2 overexpression and/or gene amplification by immunohistochemistry and by fluorescence in situ hybridization. However, clinical trials have also demonstrated the efficacy of anti-HER2 drugs against activating ERBB2/HER2 mutations in a variety of solid tumor types, and fam-trastuzumab deruxtecan is now approved by the US Food and Drug Administration for HER2-mutant non-small cell lung cancer. This study aimed at evaluating the detailed clinical, histomorphological, immunohistochemical, and molecular characteristics of gynecologic malignancies with ERBB2/HER2 mutations. We identified 16 tumors with 19 ERBB2/HER2 mutations in our departmental archives: 11 endometrial primaries, 2 endocervical adenocarcinomas, 1 ovarian mucinous adenocarcinoma, 1 tubo-ovarian undifferentiated carcinoma, and 1 high-grade endometrioid adenocarcinoma of Mullerian origin. ERBB2/HER2 mutations most often involved the tyrosine kinase domain (52.6%), and the most frequent specific mutation was R678Q (31.6%), involving the juxtamembrane domain. More than half (54.5%) of endometrial carcinomas and half of all tumors were MMR-deficient, resulting from MSH6 loss in all but 2 tumors. None of the tumors (0%) were POLE-mutated, while 18.8% were TP53-mutated. HER2 IHC was negative (score 0 or 1+) in 12 tumors (67%) and equivocal (score 2+) in 4 tumors (33%), whereas none of the tumors were scored as HER2 3+. Score 2+ was associated with R678Q, L755S, I767M mutations, and ERBB2/HER2 rearrangement with a breakpoint in exon 23. Concurrent ERBB2/HER2 amplification was identified in 2 endometrial carcinomas, with HER2/CEP17 ratios of 3.1 and 3.5. We also queried the cBioportal database, which revealed 70 ERBB2/HER2-mutant gynecologic tumors with a total of 77 ERBB2/HER2 mutations, most often involving the active site of the tyrosine kinase domain (n=36; 46.8%), and the most common specific mutation was S310F (n=20; 26%), located in the extracellular domain. Our results provide important details regarding the clinicopathological and molecular associations of potentially actionable ERBB2/HER2 mutations in endometrial carcinoma and other gynecological cancer types and contribute to addressing clinical treatment needs and improving pathology testing recommendations in the future.

Preclinical in vitro and in vivo activity of the RAF/MEK clamp avutometinib in combination with FAK inhibition in uterine carcinosarcomas.

OBJECTIVES: Uterine carcinosarcomas (UCS) are rare, biologically aggressive tumors. Since UCS may harbor mutations in RAS/MAPK pathway genes we evaluated the preclinical in vitro and in vivo efficacy of the RAF/MEK clamp avutometinib in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718 against multiple primary UCS cell lines and xenografts. METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic landscape of 5 primary UCS cell lines. The in vitro activity of avutometinib ± FAK inhibitor was evaluated using cell viability and cell cycle assays against primary UCS cell lines. Mechanistic studies were performed using western blot assays while in vivo experiments were completed in UCS tumor bearing mice treated with avutometinib ± FAK inhibitor by oral gavage. RESULTS: WES results demonstrated multiple UCS cell lines harbor genetic alterations including KRAS, PTK2, BRAF, MAP2K, and MAP2K1, potentially sensitizing to FAK and RAF/MEK inhibition. Four out of five of the UCS cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition when used alone or in combination. By western blot assays, exposure of UCS cell lines to the combination of defactinib/avutometinib demonstrated decreased phosphorylated (p)-FAK as well as decreased p-ERK. In vivo, the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition and longer survival compared to single agent treatment and controls starting at day 10 (p < 0.002) in UCS xenografts. CONCLUSION: The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and ß-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Preclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer.

OBJECTIVES: Low-grade-serous-ovarian-carcinoma (LGSOC) is characterized by a high recurrence rate and limited therapeutic options. About one-third of LGSOC contains mutations in MAPK pathway genes such as KRAS/NRAS/BRAF. Avutometinib is a dual RAF/MEK inhibitor while defactinib and VS-4718 are focal-adhesion-kinase-inhibitors (FAKi). We determined the preclinical efficacy of avutometinib±VS-4718 in LGSOC patient-derived-tumor-xenografts (PDX). METHODS: Whole-exome-sequencing (WES) was used to evaluate the genetic fingerprint of 3 patient-derived LGSOC (OVA(K)250, PERIT(M)17 and A(PE)148). OVA(K)250 tissue was successfully xenografted as PDX into female CB17/lcrHsd-Prkdc/SCID-mice. Animals were treated with either control, avutometinib, VS-4718, or avutometinib/ VS-4718 once daily five days on and two days off through oral gavage. Mechanistic studies were performed ex vivo using avutometinib±defactinib treated LGSOC tumor samples by western blot. RESULTS: WES results demonstrated wild-type KRAS in all 3 LGSOC. OVA(K)250 PDX showed gain-of-function mutations (GOF) in PTK2 and PTK2B genes, and loss-of-heterozygosity in ADRB2, potentially sensitizing to FAK and RAF/MEK inhibition. The combination of avutometinib/ VS-4718 demonstrated strong tumor-growth inhibition compared to controls starting at day 9 (p < 0.002) in OVA(K)250PDX. By 60 days, mice treated with avutometinib alone and avutometinib/VS-4718 were still alive; compared to median survival of 20 days in control-treated mice and of 35 days in VS-4718-treated mice (p < 0.0001). By western-blot assays exposure of OVA(K)250 to avutometinib, FAKi defactinib and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-ERK. CONCLUSION: Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID.

Up to 30 % of COVID-infected patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC), a syndrome characterized by a variety of debilitating symptoms lasting for more than 3 months after the acute infection. While the pathophysiological mechanisms behind PASC/LC are not completely understood, growing evidence suggests that an important component of this syndrome may be related to persistent microvascular inflammation causing clumping/clotting of red blood cells and platelets and thrombotic complications. We retrospectively evaluated the plasma levels of von Willebrand factor (VWF), Factor VIII and D-dimer in 10 gynecologic patients (60 % with an endometrial or ovarian cancer diagnosis) affected by PASC/LC vs 5 control patients (60 % harboring endometrial or ovarian tumors). We found elevated VWF and Factor VIII levels in all 10 PASC/LC patients (means of 254 % and 229 %, respectively) vs none of the 5 randomly selected cancer control patients (means of 108 % and 95 %, respectively), p = 0.0046 and p < 0.0001, respectively. In contrast, no significant difference was noted in the levels of D-dimer in PASC/LC. Importantly, abnormally elevated VWF and Factor VIII levels were found to persist for at least 2 years in patients with Long COVID symptoms. VWF and Factor VIII but not D-dimer levels are significantly elevated in the plasma of PASC/LC cancer patients. Abnormally and persistently elevated VWF and Factor VIII levels may represent the results of persistent microvascular damage (i.e., spike-induced endotheliosis) and may be biomarkers of persistent inflammation in gynecologic patients with PASC/LC.

Sialylated Glycan Bindings from SARS-CoV-2 Spike Protein to Blood and Endothelial Cells Govern the Severe Morbidities of COVID-19.

Consistent with well-established biochemical properties of coronaviruses, sialylated glycan attachments between SARS-CoV-2 spike protein (SP) and host cells are key to the virus's pathology. SARS-CoV-2 SP attaches to and aggregates red blood cells (RBCs), as shown in many pre-clinical and clinical studies, causing pulmonary and extrapulmonary microthrombi and hypoxia in severe COVID-19 patients. SARS-CoV-2 SP attachments to the heavily sialylated surfaces of platelets (which, like RBCs, have no ACE2) and endothelial cells (having minimal ACE2) compound this vascular damage. Notably, experimentally induced RBC aggregation in vivo causes the same key morbidities as for severe COVID-19, including microvascular occlusion, blood clots, hypoxia and myocarditis. Key risk factors for COVID-19 morbidity, including older age, diabetes and obesity, are all characterized by markedly increased propensity to RBC clumping. For mammalian species, the degree of clinical susceptibility to COVID-19 correlates to RBC aggregability with p = 0.033. Notably, of the five human betacoronaviruses, the two common cold strains express an enzyme that releases glycan attachments, while the deadly SARS, SARS-CoV-2 and MERS do not, although viral loads for COVID-19 and the two common cold infections are similar. These biochemical insights also explain the previously puzzling clinical efficacy of certain generics against COVID-19 and may support the development of future therapeutic strategies for COVID-19 and long COVID patients.

Increased serum 1,25-dihydroxyvitamin D levels in gynecologic cancer patients with Post-Acute-Covid-Sequela (PASC)/Long COVID.

Post-acute sequelae of COVID-19 (PASC), also known as Long-Covid (LC), may affect 10-30 % of COVID-infected patients, and is characterized by a variety of debilitating symptoms lasting over 3 months after the acute infection, including but not limited to dyspnea, fatigue, and musculoskeletal, cognitive, and/or mental health impairments. Vitamin D is an essential nutrient primarily recognized for its role in regulating calcium and bone health but also endowed with potent anti-inflammatory activity affecting a variety of immune cells. We retrospectively evaluated the plasmatic levels of both 1,25-dihydroxyvitamin-D (1,25 OH), and 25-hydroxyvitamin-D (25 OH), the active and storage forms of vitamin-D3, respectively, in the serum of gynecologic cancer patients affected by PASC/LC vs control cancer patients. We found elevated 1,25-dihydroxyvitamin-D levels in 5 out of 5 of the PASC/LC patients (mean ± SD = 97.2 ± 26.9 pg/mL) versus 0 out of 10 of randomly selected cancer control patients (44.9 ± 17.2 pg/mL, p = 0.0005). In contrast, no significant difference was noted in the levels of 25-dihydroxyvitamin-D in PASC/LC (mean ± SD = 48.2 ± 15.8 ng/mL) versus controls (43.0 ± 11.6 ng/mL, p = 0.48). Importantly, abnormal levels of vitamin D were found to persist for at least 2 years in patients with long covid symptoms. The active form (1,25OH) but not the storage form (25 OH) of vitamin-D is significantly elevated in PASC/LC cancer patients. Abnormally and persistently elevated 1,25OH levels, similarly to sarcoidosis patients, may represent the results of extrarenal conversion of vitamin D by activated macrophages, and a novel biomarker of persistent inflammation in gynecologic cancer patients with PASC/LC.

Antibody-Drug Conjugates (ADC) in HER2/neu-Positive Gynecologic Tumors.

Antibody-drug conjugates (ADCs) are a new class of targeted anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a highly cytotoxic molecule payload bonded through specifically designed cleavable or non-cleavable chemical linkers. One such tumor surface receptor is human epidermal growth factor 2 (HER2), which is of interest for the treatment of many gynecologic tumors. ADCs enable the targeted delivery of a variety of cytotoxic therapies to tumor cells while minimizing delivery to healthy tissues. This review summarizes the existing literature about HER2-targeting ADC therapies approved for use in gynecologic malignancies, relevant preclinical studies, strategies to address ADC resistance, and ongoing clinical trials.

Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100.

OBJECTIVE: This prespecified exploratory analysis evaluated the association of gene expression signatures, tumor mutational burden (TMB), and multiplex immunohistochemistry (mIHC) tumor microenvironment-associated cell phenotypes with clinical outcomes of pembrolizumab in advanced recurrent ovarian cancer (ROC) from the phase II KEYNOTE-100 study. METHODS: Pembrolizumab-treated patients with evaluable RNA-sequencing (n = 317), whole exome sequencing (n = 293), or select mIHC (n = 125) data were evaluated. The association between outcomes (objective response rate [ORR], progression-free survival [PFS], and overall survival [OS]) and gene expression signatures (T-cell-inflamed gene expression profile [TcellinfGEP] and 10 non-TcellinfGEP signatures), TMB, and prespecified mIHC cell phenotype densities as continuous variables was evaluated using logistic (ORR) and Cox proportional hazards regression (PFS; OS). One-sided p-values were calculated at prespecified α = 0.05 for TcellinfGEP, TMB, and mIHC cell phenotypes and at α = 0.10 for non-TcellinfGEP signatures; all but TcellinfGEP and TMB were adjusted for multiplicity. RESULTS: No evidence of associations between ORR and key axes of gene expression was observed. Negative associations were observed between outcomes and TcellinfGEP-adjusted glycolysis (PFS, adjusted-p = 0.019; OS, adjusted-p = 0.085) and hypoxia (PFS, adjusted-p = 0.064) signatures. TMB as a continuous variable was not associated with outcomes (p > 0.05). Positive associations were observed between densities of myeloid cell phenotypes CD11c+ and CD11c+/MHCII-/CD163-/CD68- in the tumor compartment and ORR (adjusted-p = 0.025 and 0.013, respectively). CONCLUSIONS: This exploratory analysis in advanced ROC did not find evidence for associations between gene expression signatures and outcomes of pembrolizumab. mIHC analysis suggests CD11c+ and CD11c+/MHCII-/CD163-/CD68- phenotypes representing myeloid cell populations may be associated with improved outcomes with pembrolizumab in advanced ROC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02674061.