Advanced Malignancies Research Articles

Perioperative outcomes and survival of modified subxiphoid video-assisted thoracoscopic surgery thymectomy for T2-3 thymic malignancies: A retrospective comparison study

ObjectiveOur previous study demonstrated that modified subxiphoid video-assisted thoracic surgery thymectomy with an auxiliary sternal retractor is feasible for locally invasive thymic malignancies. This study aimed to compare perioperative and oncological outcomes of modified subxiphoid video-assisted thoracoscopic surgery thymectomy versus median sternotomy thymectomy for locally advanced thymic malignancies. MethodsIn total, 221 patients with T2-3 thymic malignancies who underwent modified subxiphoid video-assisted thoracoscopic surgery thymectomy or median sternotomy thymectomy between 2015 and 2020 were enrolled in our prospectively maintained database. A 1:1 propensity score–matching analysis was performed to balance the bias. Surgical difficulty was evaluated with a modified resection index. Perioperative and oncological results were compared between the modified subxiphoid video-assisted thoracoscopic surgery thymectomy group and the median sternotomy thymectomy group. ResultsThere were 72 patients in each group in the final analysis. Our results showed that the modified subxiphoid video-assisted thoracoscopic surgery thymectomy group had a shorter operative duration (98 vs 129 minutes, P < .001), less blood loss (40 vs 100 mL, P < .001), shorter drainage duration (3 vs 5 days, P < .001), shorter length of hospital stay (5 vs 6 days, P < .001), and fewer postoperative complications (5.6% vs 23.6%; P = .005). No significant difference was detected in complete resection (98.6% vs 98.6%, P = 1.000) between the 2 groups. Conversion occurred in 5 of 106 patients (4.7%). Survival analyses indicated similar recurrence-free survival (hazard ratio, 0.94; 95% CI, 0.40-2.20; P = .883) and overall survival (hazard ratio, 0.52; 95% CI, 0.05-5.02; P = .590) between the 2 groups. ConclusionsModified subxiphoid video-assisted thoracoscopic surgery thymectomy was safe and effective for T2-3 thymic malignancies and could be an alternative for selected patients with locally advanced thymic diseases. Further prospective studies are needed to evaluate the long-term survival of those undergoing modified subxiphoid approach thoracoscopic thymectomy.

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

#31. A Phase I/II trial of ATI-2231 with Phase Ia in advanced soild tumor malignancies followed by Phase Ib/II in combination with capecitabine in patients with hormone receptor-positive (HR+) and HER2-negative metastatic breast cancer

#31. A Phase I/II trial of ATI-2231 with Phase Ia in advanced soild tumor malignancies followed by Phase Ib/II in combination with capecitabine in patients with hormone receptor-positive (HR+) and HER2-negative metastatic breast cancer

Off‐label use of rituximab for dermatologic conditions: A single center review

AbstractBackgroundRituximab (RTX) has been utilised off‐label for a variety of dermatological indications beyond pemphigus vulgaris. Efficacy has been reported in other immunobullous disorders, inflammatory dermatoses and connective tissue diseases.ObjectivesTo assess the off‐label use of RTX in our centre with respect to indications, frequency and duration of treatment, efficacy, and adverse events.MethodsCharts were retrospectively reviewed for all patients who received dermatologist‐prescribed RTX infusions off‐label at our centre between 2009 and 2022. Efficacy was categorised based on reported percentage reduction of disease activity: very good (75%–100%), good (50%–74%), partial (25%–49%) and none (0%–24%).ResultsTwenty‐nine patients received RTX off‐label during this time period. Infusions were discontinued in 28% (n = 8), due to insufficient clinical response. Median treatment duration for those on 6‐12‐monthly regular infusions was 2.4 years (range 0.5–11 years). Indications included cutaneous lupus (n = 9), mucous membrane pemphigoid (n = 5), pyoderma gangrenosum (n = 6), lichen planus (n = 2), dermatomyositis (n = 1), livedoid vasculitis (n = 1), sarcoidosis (n = 1), bullous pemphigoid (n = 1), pemphigus vulgaris, foliaceus and vegetans (n = 1 each). Clinical improvement was documented in 79% (n = 23); very good in 48% (n = 14), good in 17% (n = 5), and moderate in 14% (n = 4). Clinical efficacy in immunobullous disorders was 100% (9/9), 67% in cutaneous lupus (6/9), 33% in pyoderma gangrenosum (2/6), and 50% in lichen planus (1/2). No side effects were documented for 79% (n = 23). Adverse peri‐infusion events were seen in three patients (10%). Four patients died during follow up; one due to neutropenic sepsis with a background of advanced malignancy, and three due to Covid‐19. ConclusionsRTX was prescribed for multiple off‐label dermatological indications, often for recalcitrant disease. Responses were good overall, with a reassuring safety profile. Three patients died of Covid‐19; knowledge of the impact of RTX on the immune response and efficacy of vaccines is expanding and will continue to inform guidelines for RTX use in the post‐Covid era.

Short-term outcomes of posterior surgery for thoracolumbar spinal metastasis

Purpose The purpose of the work is to evaluate the postoperative quality of life, neurological condition, and ambulatory status of patients with spinal metastases treated surgically during the first year after surgery in countries with limited resources. Methods This was a prospective case series study. All patients with spinal metastasis and indicated for surgery, presented to our facility from 2020 to 2021 were included in the study. Clinical evaluation includes visual analog score (VAS) for back pain, the Frankel grading system for neurological assessment, the Tokuhashi severity and survival score for predicting the expected patient survival period, and the 5Q-ED score for assessment of quality of life. Results This study included 30 patients with thoracolumbar spine metastasis who underwent surgery, 21 males and 9 females in the age range of between 18 and 72 years with a median value of 49.17 ± 13.272 years. Five patients died within 6 months postoperatively due to advanced malignancy, while the remaining 25 patients were followed-up for at least 1 year. Conclusion Surgical treatment for metastatic spinal tumor can improve quality of life in a substantially high percentage of patients with acceptable complication rates in a limited resource setting. Spinal surgery for metastatic cancer significantly reduces pain and is effective in preserving neurological function over short-term follow-up with acceptably low morbidity. The Tokuhashi score (especially primary site of malignancy) had a significant effect on overall survival.

Palliative care for patients with hematologic malignancies in Germany: a nationwide survey on everyday practice and influencing factors from the perspective of treating physicians

Integrating palliative care into the treatment of patients with advanced hematological malignancies (HM) remains challenging. To explore treating physicians’ perspectives on current palliative care practice and to evaluate factors influencing integration, we conducted a nationwide online survey. Based on literature and expert review, the survey addressed the importance of palliative care, communication about life-threatening conditions, challenges in establishing goals of care, and factors influencing the integration of palliative care. 207 physicians treating patients with HM in Germany participated. We used standard descriptive statistics to analyze quantitative data and a content structuring approach. Most physicians considered palliative care in HM to be very important (60.6%) and discussed life-threatening conditions with more than half of their patients (52%), especially when goals of care were changed (87.0%) or when patients raised the topic (84.0%). Disease-related factors, different professional perspectives on prognosis, and patient hopes were the main barriers to changing goals of care, but collaboration with colleagues and multidisciplinary teams provided important support. Time constraints were identified as the main barrier to integrating palliative care. The majority worked well with palliative care teams. Referral processes and conditions were perceived as minor barriers. The study highlights the need to address barriers to integrating palliative care into the management of patients with advanced HM. Future research should aim at optimizing palliative care for patients with HM.

Abstract 5707: Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies

Abstract KRLS-017 is a potent, selective, and reversible inhibitor of Cyclin Dependent Kinase 7 (CDK7). Its molecular formula is C24H35N5O2Si and its molecular weight is 453.65 Daltons. KRLS-017 is being developed for the treatment of patients with advanced solid tumor malignancies. To differentiate KRLS-017 from other CDK7 inhibitors, we created a reversible inhibitor to allow for treatment schedule optimization and maximization of therapeutic index in clinic. High selectivity of KRLS-017 for CDK7 was confirmed using a panel of 313 recombinant human kinases. The IC50 of KRLS-017 against recombinant human CDK7 was determined to be 16 nM, and no other kinases in the panel showed IC50 values less than 300 nM. Antiproliferative activity of KRLS-017 was investigated in vitro using a broad panel of human tumor cell lines. KRLS-017 showed potent antiproliferative effect across a wide variety of both solid and hematologic tumor types, producing GI50 values &amp;lt;200 nM in 258/302 human tumorcell lines tested. Antitumor activity of KRLS-017 was investigated in vivo using multiple mouse xenograft tumormodels at dose levels ranging from 25 mg/kg to 200 mg/kg using both continuous (daily) andintermittent dosing schedules. Statistically significant tumor growth inhibition was seen at doselevels of 50 mg/kg and higher, with tumor regression observed at 100 mg/kg and 200 mg/kg. Better in vivo tolerability at efficacious doses was observed using intermittent dosing schedules in mouse xenograft models, which led to adoption of an intermittent schedule in the proposed first-in-human phase 1 trial. KRLS-017 is orally bioavailable in mice, rats, and dogs and plasma drug exposure increased in a proportional manner with dose. Comparing first dose and 28th dose in the dog, minimal plasma accumulation was observed, suggesting once daily dosing in humans would be initially tested. Repeat dose 28 day GLP toxicology studies in rat and dog showed adverse effects in highly proliferative bone marrow and gastrointestinal tissues which is consistent with the known mechanism of action for CDK7 and is considered to be monitorable and manageable in the setting of oncology. The clinical development plan for KRLS-017 includes an initial Phase 1 dose escalation study (KRLS-017-101) in patients with refractory solid tumor malignancies to assess pharmacokinetics/pharmacodynamics and to determine an optimal dose level and treatment schedule to test in expansion cohorts. Given the potential of CDK7 inhibitors in the treatment of hormone receptor positive breast cancer, combination work with other agents (such as selective estrogen receptor degraders) is on-going. Citation Format: Alison L. Hannah, Steve Ritland, Thomas Steele, Steven Smith, Ashwin Ram, BT Slingsby, Kapil Dhingra, James Chrisman, Rajesh Dua, Yasunori Tokunaga, Shigeyuki Kono, Yasuhiro Aga. Preclinical evaluation of KRLS-017, a potent, highly selective and reversible CDK7 inhibitor with broad antitumor effect in preclinical models, in preparation for a Phase 1 clinical trial in advanced solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5707.

Abstract 5001: Personalized neoantigen/cancer-testis antigen nanovaccine for advanced solid tumors, a single-arm, open-label pilot study

Abstract Background: Neoantigens, derived from somatic mutations in tumor cells, have been identified as promising targets of immunotherapy. A personalized neoantigen/cancer-testis antigen (CTA) nanovaccine (PNVAC) platform has been established by us previously, and demonstrated its feasibility, safety and efficacy in preventing recurrence of high-risk resected gastric/gastroesophageal junction (G/GEJ) cancer in both preclinical and clinical studies. This study aims to explore the universality of PNVAC monotherapy or combined with anti-angiogenesis drugs or anti-programmed death 1 (PD-1) in patients with multiple advanced solid malignancies. Methods: Patient-specific neoantigens were selected based on tumor-specific mutations identified by whole-exome sequencing (WES) and RNA sequencing of paired blood and tumor tissues. Bioinformatic analysis for neoantigen prediction, including sequencing read filtering, human leukocyte antigen (HLA) typing and neoantigen filtering was performed. PNVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens designed to induce specific T cell responses. PNVAC is administrated to patients with metastatic solid tumors on days 1, 4, 8, 15, 22, 43 (prime phase) and 64, 85 and 169 (boost phase) alone, or combined with anti-angiogenesis or anti-PD-1 drugs. Safety, immunogenicity and clinical efficacy are evaluated. Results: Of the 30 enrolled patients, no treatment-related severe adverse events (AEs) occurred and the vast majority of AEs were limited to grade 1-2, only 1 patient developed grade 3 thrombocytopenia. The objective response rate (ORR) was 26.7% (8/30), including 2 cases of complete response (CR) and 6 cases of partial response (PR), and a disease control rate (DCR) of 66.7% achieved. The median progression-free survival (PFS) was 9.90 months (95% CI, 3.46-16.34 months), while the median overall survival (OS) was not reached (range, 0.80-43.53 months), and the estimated 1- and 2-year survival rates were 86.2% and 60.6%. Notably, among the 21 patients who had relapsed disease after previous ICB and/or anti-angiogenesis, disease control was asserted in 14 (66.7%) of them (7 of SD, 5 of PR, 2 of CR). ORR of this set was 33.3% (7/21), higher than that of all the enrolled patients (26.7%), and the set without prior ICB and/or anti-angiogenesis treatment (11.1%). For immune analysis, PNVAC elicited robust and persistent immune responses against neoantigens/CTAs. Additionally, peripheral T cells with a cytotoxic phenotype tended to increase after vaccination, and immune memory was also detected in some representative patients. Conclusions: These data supported the safety, immunogenicity, and efficacy of this regimen in patients with advanced solid malignancies, thus broadening the application and combined strategies of neoantigen-based vaccines. Clinical trial information: ChiCTR1800017319. Citation Format: Jia Wei, Qin Liu, Lijing Zhu, Jie Shao, Ju Yang, Guanghui Xu, Nandie Wu, Hanbing Wang, Rutian Li, Huizi Sha, Qiuping Xu, Jie Shen, Li Xie, Lifeng Wang, Juan Du, Lanqi Cen, Manman Tian, Lixia Yu, Baorui Liu. Personalized neoantigen/cancer-testis antigen nanovaccine for advanced solid tumors, a single-arm, open-label pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5001.

Abstract 2359: New insights into targeting the CD200R1 pathway in T and NK cells using 23ME-00610 as a single agent or in combination

Abstract 23ME-00610 is a monoclonal antibody that is being evaluated as a single agent in a Phase 1/2a clinical trial for advanced solid malignancies (NCT05199272). It binds with high affinity (KD &amp;lt; 0.1 nM) to CD200R1, a promising immune-oncology (IO) target identified by surveying the 23andMe genetic and health survey database. CD200R1 is an inhibitory receptor that when bound to its ligand CD200, reduces pro-inflammatory cytokine production, and leads to an immunosuppressive tumor environment. To gain further insight into the mechanism of action of 23ME-00610 and its potential for combination therapy, we profiled CD200R1 and other immune inhibitory receptors in human dissociated solid tumor samples using spectral flow cytometry. CD200R1 was broadly expressed across tumor-infiltrating immune cells, including T cells and NK cells, cytotoxic cell types with known antitumor functions. Notably, CD200R1 expression pattern was differentiated from PD-1, which is mostly restricted to T cells, indicating differences in patient populations that could potentially benefit from anti-CD200R1 and anti-PD-1 treatments. The ligand, CD200 was broadly expressed, including on tumor cells and endothelial cells. The differential expression profiles of CD200R1 and PD-1 on immune cells, along with CD200 expression on endothelial cells, suggest that combining 23ME-00610 with other clinically validated immunomodulatory agents could enhance antitumor responses. Follow-up experiments were conducted to validate and extend these findings. In an in vitro assay with cancer patient-derived PBMCs, 23ME-00610 promoted higher production of IFNγ, a key functional antitumor cytokine, compared to anti-PD-1 in 9 of 10 donors. Subsequent attempts were made to pinpoint immune cells responsible for 23ME-00610's anti-tumor activity. 23ME-00610 reversed CD200-mediated suppression of chronically stimulated primary T cells and CD200-mediated inhibition of NK cell degranulation, suggesting that 23ME-00610 can mediate tumor cell killing through at least two different cell types. To test the potential of 23ME-00610 to combine with anti-PD-1 to enhance T cell function, an artificial antigen-presenting cell (aAPC) line overexpressing PD-L1 and CD200 was co-cultured with chronically stimulated primary human T cells. Anti-PD-1 and 23ME-00610 each independently enhanced IFNy secretion levels compared to isotype control, yet their combination resulted in a more than additive effect. Taken together, these data demonstrate that 23ME-00610 can enhance both NK and T cell antitumor effector functions, and 23ME-00610 could synergize with anti-PD-1 to further increase the activity of T cells against cancer cells. The results of this study provide evidence that 23ME-00610 could expand IO treatment options for patients with advanced solid malignancies as a single agent or in combination with other anti-tumor therapeutics. Citation Format: Mithra R. Kumar, Shiteng Duan, Shruti Yadav, Abigail Jarret, Zhonghao Yan, Jill Fenaux, Martin Kinisu, Zuoan Yi, Mauro Poggio, Patrick Collins, Antony Symons, Lorena Riol Blanco, Maike Schmidt, Sophia Majeed, Anh Diep, Clarissa Lee. New insights into targeting the CD200R1 pathway in T and NK cells using 23ME-00610 as a single agent or in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2359.

Abstract 1886: BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics

Abstract LIV-1, also known as SLC39A6 or ZIP6, belongs to the zinc transporter family and was initially identified as an estrogen-inducible gene in breast cancer. Immunohistochemical (IHC) analysis have revealed escalated LIV-1 expression in estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) as well as ER-/PR-/Her2- (triple-negative) breast cancers. Notably, healthy human tissues exhibit limited LIV-1 expression, primarily in hormone regulated organs (prostate, uterus, and breast). The escalated expression of LIV-1 in breast and prostate cancer, as well as melanoma and other tumors, positions LIV-1 as an excellent target for ADC therapeutics. BRY812 is a monomethyl auristatin E (MMAE)-conjugated humanized IgG1 ADC against LIV-1. With Bioray’s irreversible conjugation method CysLinkTM, BRY812 enables superior in vivo stability and eliminates off-target payload migration. The PK studies in rat and monkey demonstrated that the free MMAE released from ADC is 1 to 2 logs lower compared with approved ADCs prepared by the standard conjugation method. BRY812 is well tolerated in cynomolgus monkeys with repeated doses. With best-in-class anti-tumor efficacy in various models, BRY812 demonstrated a wider therapeutic window for cancer treatment. BRY812 is currently in Phase Ia dose escalation stage clinical trial to explore the maximum tolerate dosage (MTD) from 0.25 to 3.6 mg/kg Q3W in patients with advanced malignancies. Citation Format: Xiaobei Zhao, Jie Zhu, Yaqiong Zhou, Jing Li, Lei Nie, Haibin Wang, Gang Chen. BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1886.

Abstract 3186: An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study

Abstract Background: Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, yet resistance to this therapy can lead to immune escape and disease progression. Here, we introduce WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 naturally accumulates in the spleen and remodels the splenic immune landscape in tumor-bearing mice. Pre-clinical studies have demonstrated that T cells activated by WTX-212 reduce the splenic reservoir of immunosuppressive myeloid cells, including those within tumors. This results in a systemic anti-tumor immune response and suppression of tumor growth in xenograft tumor models resistant to anti-PD-1 immunotherapies. A first-in-human (FIH) clinical trial is now investigating its potential in human cancer patients. Methods: The FIH trial (NCT05707325) is aimed to investigate the safety, pharmacokinetics, mechanisms and preliminary efficacy of WTX-212 in cancer patients with advanced malignancies. All of patients had previously received anti-PDs therapies and developed resistance to these treatments. By November 15th, 2023, 7 patients across two cohorts had received WTX-212 monotherapy (1 × 1011-2 × 1011 cells, Q3W IV). The tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. No dose-limiting toxicities or treatment-related adverse events greater than Grade 3 were reported. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control, including partial remission (PR) and stable disease (SD), was observed in 5/7 patients (DCR, 71%). One patient with esophageal cancer achieved a PR with a significant 44% reduction in target lesion size after two cycles of treatment. Two patients, one with esophageal cancer (3 lines prior therapies) and another with HPV-negative cervical cancer (4 lines prior therapies), maintained disease control for over 30 weeks after WTX-212 treatment. Consistent with preclinical findings, WTX-212 systemically induced anti-tumor responses, leading to a reduction of myeloid-derived suppressor cells (MDSCs) particularly the PMN-MDSC subset in 6/7 patients (reductions ranging from 24%-82% compared to baseline), and a median 1.5-fold increase of T cells in 7/7 patients in the peripheral blood after the 1st cycle of treatment. Conclusion: The initial promising data support further investigation and exploration of the combination therapy strategies to expand the therapeutic potential of WTX-212 in cancer patients. Erythrocyte-drug conjugation may serve as a unique strategy for targeting the peripheral immune system to treat cancers. Citation Format: Liu Yang, Xiaoqian Nie, Zheling Chen, Yuehua Liu, Jiawei Zheng, Xiaofei Gao. An Erythrocyte-αPD-1 conjugate suppresses cancers resistant to checkpoint blockade immunotherapy: A first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3186.

Abstract 7537: “Cross-over Effect” in survival curves with immune-checkpoint inhibition: Identifying ideal candidates for immunotherapy-only approaches in specific tumor histologies

Abstract Immune checkpoint inhibition (ICI), a cornerstone of modern immunotherapy (IO), has revolutionized cancer treatment, offering significant survival benefits across various malignancies. Initial trials with ICI in refractory cancers demonstrated remarkable efficacy compared to standard-of-care (SOC) treatments. With the integration of ICI into combination therapies, including chemotherapy and multi-tyrosine kinase inhibitors (TKI), its role in frontline, early-stage, and locally advanced cancers has grown. However, the potential of an immunotherapy-only strategy, especially in advanced malignancies, warrants better biomarker selected approaches given the inconsistencies with existing biomarkers. This study investigates the "cross-over” effect observed in Kaplan-Meier survival curves from randomized trials comparing ICI with non-ICI agents where the survival curves, assumed to be proportionally constant distinctly cross over each other during the on-treatment monitoring period. We initiated a meta-analysis investigating randomized trials comparing ICIs with non-ICI historical SOC agents and finally analyzed data from 38 large clinical trials. Trials were selected based on their comparative nature with overall survival (OS) and progression-free survival (PFS) data as outcomes. A positive “cross-over” in Kaplan-Meier curves was identified when divergence occurred for at least three consecutive months. Cross-over in PFS and OS curves were observed in 53% (20/38) and 43% (16/37) of trials, respectively. All cross-overs were one-sided with the ICI arm crossing over the non-ICI arm with a superior tail. Notably, 100% of trials with OS curve cross-over involved ICIs against chemotherapy. A significant association (Fischer’s exact test, p=0.01) was found between OS curve cross-over and adenocarcinoma histologies, in contrast to trials with no cross-over effect, predominantly featuring squamous cell carcinomas. This pattern persisted within various organ sites such as the lung, esophagus, and cervix where both adenocarcinomas and squamous histological patterns are seen. Cross-over of Kaplan-Meier curves blatantly violates the cox-proportional hazard assumption, potentially underestimating the impact of the ICI-only approach compared to alternative therapies. These observations highlight substantial biological heterogeneity in tumor responses to ICI versus chemotherapy. The cross-over effect, particularly pronounced in gland-forming tumors (adenocarcinomas), underscores the urgent need to investigate mechanisms of ICI resistance in these tumor types and incorporate tumor histology and longitudinal tumor growth dynamics into existing predictive models for biomarkers for IO response and help identify patients who would benefit the most from immunotherapy-only approaches. Citation Format: Shubhank Goyal, Anish Thomas, Parth Anil Desai. “Cross-over Effect” in survival curves with immune-checkpoint inhibition: Identifying ideal candidates for immunotherapy-only approaches in specific tumor histologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7537.

Abstract 2857: Perspectives from a systematic review of kinase fusion oncogenes and access to corresponding kinase inhibitor clinical trials in pediatric, adolescent, and young adult solid malignancies

Abstract Oncogenic kinase fusions (KFs) have been reported in pediatric, adolescent, and young adult (P-AYA) brain tumors, sarcomas, and rare solid malignancies. Molecularly targeted therapy (MTT) matched to KFs generally produce objective responses even in advanced P-AYA malignancies. KFs occur across a broad age range of P-AYA cancer diagnoses (dx) so data on KF prevalence and the relationship between KFs and clinical characteristics including response and resistance to MTT is distributed across many studies. To address resulting knowledge gaps, we conducted a systematic review of KFs reported in P-AYA cancers and assessed the availability of clinical trials (CTs) for P-AYA patients with KF malignancies. A systematic literature search was conducted with PubMed using publication date 2013-2022, search terms for dx, age, and gene names of interest (BRAF, RAF1, NTRK1-3, ALK, FGFR1-4, MET, RET, ROS1). Known P-AYA cancer sequencing studies were also reviewed. Papers were included if they reported ≥1 patient &amp;lt;18 yo with a KF cancer of any type or ≤30 yo with a KF P-AYA cancer dx. Data abstracted included paper type, KF gene and partner, dx, fusion breakpoints, age, stage, MTT received, response to MTT, and CT enrollment. Clinicaltrials.gov was queried for interventional CTs in the U.S. assessing relevant MTTs. We identified 531 studies (299 case reports/series; 119 P-AYA sequencing studies) reporting 4,329 patients with a KF P-AYA solid tumor. Brain tumors had, in decreasing order of frequency, BRAF, NTRK, FGFR, ALK, ROS1, RAF1, MET, and RET fusions. Dx in which KFs were reported were LGG (n=2451), HGG (n=298), embryonal tumors (n=16), ependymomas (n=8), meningioma (n=1), and other (n=16). Extracranial solid tumors (EST) had, in decreasing order of frequency, NTRK, RET, ALK, BRAF, ROS1, MET, FGFR, and RAF1 fusions. Dx in which KFs were reported were thyroid cancer (n=607), sarcoma (n=546), melanoma and spitz tumor (n=183), renal tumor (n=90), carcinoma (n=57), rhabdomyosarcoma (n=12), neuroblastoma (n=11), osteosarcoma (n=9), and other (n=24). As of Aug 23, 2023, 476 CTs were assessing 65 inhibitors relevant for these KFs, of which only 20 are currently FDA-approved. Patients &amp;lt;18 yo were only eligible for 16% of CTs. RET (47%), RAF/BRAF (33%), and NTRK (32%) inhibitors had the highest percent of CTs enrolling patients &amp;lt;18 yo while ERK (4%) and FGFR (6%) inhibitors had the least. Notably, while 467 P-AYA patients identified in our review were &amp;lt;18 yo and had an ALK- or ROS1-fusion positive tumor, only 24% of ALK or ROS1 inhibitor CTs allowed enrollment of patients &amp;lt;18 yo. To our knowledge, this is the first systematic review of KFs in P-AYA solid tumors. Oncogenic KFs are common and occur across P-AYA solid and brain tumor dx demonstrating a need for CTs of relevant MTTs including patients &amp;lt;18 yo, particularly for drugs targeting ALK, ROS1, and FGFR. Citation Format: Lorena Lazo de la Vega, Sebastian K. Eder, Ellen Sukharevsky, Zachary A. Kahn, Michaela O'Connell, Franziska Wachter, Emily P. Anderson, Maria C. Trissal, Jenna J. LaBelle, Kendall Carpenter, Leo Kager, Mariella G. Filbin, Katherine A. Janeway. Perspectives from a systematic review of kinase fusion oncogenes and access to corresponding kinase inhibitor clinical trials in pediatric, adolescent, and young adult solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2857.

Abstract 12: TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB

Abstract Chimeric antigen receptor (CAR-)/T cell receptor (TCR-)T-based immunotherapies have shown promising results in the treatment of patients suffering from hematological malignancies. However, targeting solid cancer patients with CAR-T/TCR-T cells represents a more challenging approach, due to various factors present within the hostile tumor micro-environment (TME), inhibiting T cell functionality and leading to T cell exhaustion. Programmed cell death ligand-1 (PD-L1) is expressed on tumor cells as well as various cell types within the TME and binds to programmed cell death protein 1 (PD-1) expressed on the surface of activated T cells, thereby inducing T cell exhaustion and mediating tumor immune escape. To impair this inhibitory mechanism and improve TCR-T cell efficacy for the treatment of solid tumors, we use the chimeric costimulatory switch protein (CSP) PD1-41BB that turns the inhibitory signal mediated via the PD-1-PD-L1 axis into a costimulatory one. The CSP-mediated costimulatory signal is TCR-gated, whereby costimulation can only occur if a specific peptide-HLA complex present on a target cell interacts with a recombinant TCR expressed in T cells. In vitro co-cultures of rTCR-T cells expressing the CSP (CSP rTCR-T cells) and antigen-negative or -positive cell lines carrying or lacking PD-L1 demonstrated that CSP rTCR-T cells display functionality only if the respective target antigen is expressed in target cells, but not in the absence of target antigen. PD-L1-positive, antigen-negative tumor cells are not lysed by CSP rTCR-T cells, not even in the presence of antigen-positive tumor cells, showing gated functionality and a favorable safety profile of CSP-armored TCR-T cells. CSP rTCR-T cells displayed enhanced cytokine release and killing after encounter of PD-L1-positive tumor cell lines, compared to tumor cells lacking PD-L1, and showed the capacity to recognize and lyse a large panel of tumor cell lines expressing various levels of HLA-A*02, target antigen and PD-L1 in vitro. 3D spheroids derived from PD-L1-positive, target antigen-positive tumor cell lines mimicking cell-cell interactions within a solid tumor mass efficiently triggered CSP rTCR-T cells, leading to specific IFN-γ release and lysis of tumor spheroids. Furthermore, CSP rTCR-T cells showed enhanced proliferative capacity and expansion in co-cultures with PD-L1-positive tumor cells, compared to tumor cells lacking PD-L1 expression. Importantly, various target antigen-negative healthy cell types expressing or lacking PD-L1 and representing different vital organs were not cross-recognized by CSP rTCR-T cells in vitro. Our preclinical in vitro assessments of CSP rTCR-T cell functionality and safety proved their superior and gated functionality as well as favorable safety profile, showing the great potential for the treatment of cancer patients suffering from advanced solid tumor malignancies. Citation Format: Maja Buerdek, Petra U. Prinz, Kathrin Mutze, Andrea Coluccio, Stefanie Tippmer, Miriam Bosch, Giulia Longinotti, Mario Catarinella, Kathrin Davari, Christiane Geiger, Barbara Loesch, Kirsty Crame, Dolores J. Schendel. TCR-gated control of costimulatory switch protein (CSP) activation in rTCR-T cells expressing PD1-41BB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 12.

Abstract 7539: First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity

Abstract NTX1088, a first-in-class anti-PVR (CD155) mAb, is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425). The trial initiated at MD Anderson Cancer Center, and was expanded into additional sites, including City of Hope, Ochsner Health, Sheba Medical Center and Hadassah Medical Center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 is investigated as a single agent and in combination with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with advanced solid malignancies. Ongoing dose escalation demonstrates a safe profile across ascending dose levels. NTX1088 is a high affinity humanized IgG4-S228P mAb that binds PVR and blocks all known interacting receptors at a single nM EC50. PVR, is a highly upregulated membrane protein on numerous tumor cells. PVR expression has been associated with worse patient outcome, due to its central role in immune suppression. PVR’s impact is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. PVR also interacts with the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088 has multiple immune-stimulating roles, through restoration of DNAM1 immune activation function, while simultaneously neutralizing TIGIT, CD96 and KIR2DL5A inhibitory signals in immune cells. Importantly, DNAM1 downmodulation was recently identified as a key resistance mechanism to approved immune checkpoint inhibitors, and its restoration by NTX1088 is a novel MoA, not demonstrated previously by other therapies.In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, superior to TIGIT, CD112R, and PD1 antibody blockade, leading to a greater immune-mediated tumor cell killing, IFNγ secretion, and CD137 induction. Importantly, only NTX1088 was able to restore DNAM1 to the surface of immune cells. Synergy was obtained when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13.Syngeneic models of PVRK.O, demonstrated a complete immune-mediated tumor regression. Numerous humanized murine xenograft models were investigated whereby NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade.In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on its ability to simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker analysis is showing initial mechanistic proof of concept for NTX1088 mode of action, including the restoration of DNAM1 surface expression on patients’ immune cells. This is the first case of surface DNAM1 elevation in clinical settings. Citation Format: Anas Atieh, Akram Obeidat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana Roviš, Paola Brilc, Ofer Mandelboim, Stipan Jonjic, Pini Tsukerman. First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7539.

Abstract 1193: Peripheral immune analyses from phase I trial of HPV vaccine PRGN-2009 in combination with bintrafusp alfa in patients with HPV-associated cancers

Abstract Background: PRGN-2009 is a novel gorilla adenovirus vaccine targeting HPV16/18, and bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGFβ fusion protein. Patients with pretreated advanced HPV-associated malignancies received PRGN-2009 vaccine (5 × 1011 particle units, subcutaneous administration) q2 weeks for 3 administrations and biweekly 1200mg BA followed by q4 weeks vaccine and biweekly BA (NCT04432597), with an overall response rate of 30%. We report here correlative analyses from this first-in-human Phase I study using peripheral blood from 10 patients with HPV16+ (n=8), HPV18+ (n=1), or HPV45+ (n=1) disease to identify immune correlates associated with clinical response. Methods: Peripheral HPV-specific T cell responses, HPV circulating tumor DNA (ctDNA) from plasma, serum cytokines and soluble factors, and peripheral immune cell subsets were assessed to evaluate changes induced with treatment and peripheral correlates associated with clinical activity. Patients with complete response (CR, n=1), partial response (PR, n=2; 1 confirmed) or stable disease (SD, n=1) (n=4 total) were compared to patients with progressive disease (PD, n=6). Results: Eighty percent (8/10) of patients developed either HPV16 or HPV18-specific T-cell responses after repeat administration of PRGN-2009 with BA. Eight of 10 patients had detectable HPV16 or 18 ctDNA at baseline and changes in ctDNA load with treatment generally correlated with outcomes. Early transient increases in IL-8, TNFα, and IFNγ occurred, with greater increases in IL-8 at 2 weeks and TNFα at 4 weeks in patients with PD compared to CR/PR/SD. The patient who achieved a durable CR had HPV45+ disease, and had a) a 50% increase in CD8+ T cell frequency at 2 weeks, b) increases in frequencies of CD8+ naïve T cells expressing Ki67+ and central and effector memory T cells expressing 4-1BB, PD-1, or TIM-3, and c) considerable increases in HPV18-specific T cell responses through 484 days after treatment start, indicating durable antigen-specific T cell activity. Conclusions: The majority of patients developed HPV16/18 specific T-cell responses after repeat administration of PRGN-2009 in combination with BA. Transient increases in IL-8 and TNFα 2-4 weeks after start of treatment were associated with worse outcomes, suggesting that early changes in cytokines may reflect disease course. Furthermore, the early expansion of CD8+ T cell subsets in the patient developing a CR with HPV45+ disease after receiving a vaccine targeting HPV16 and HPV18 epitopes suggest a broadening and boosting of T cell responses that enabled potent anti-tumor activity. A high degree of homology between HPV18 and HPV45 may have contributed to the expansion of HPV18 specific T cells in the patient with CR. These data highlight the importance of assessing peripheral blood in immunotherapy trials to reveal important immunological phenomena. Citation Format: Meghali Goswami, Charalampos S. Floudas, Julius Strauss, Douglas E. Brough, Amy R. Lankford, Caroline Jochems, James L. Gulley, Jeffrey Schlom, Renee N. Donahue. Peripheral immune analyses from phase I trial of HPV vaccine PRGN-2009 in combination with bintrafusp alfa in patients with HPV-associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1193.

Abstract 3072: BXQ-350: A novel biologic that allosterically activates glucosylcerebrosidase and demonstrates signs of activity in cancer patients

Abstract Background: Ceramides, glucosylceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance while glucosylceramides and S1P promote cancer cell proliferation, activate multiple oncogenic pathways, promote chemoresistance and stimulate a pro-tumoral microenvironment. Many studies have shown a better prognosis and longer survival for patients with high ceramides levels, while high S1P and glucosylceramides levels are associated with shorter survival and worst prognosis. Levels of ceramides, glucosylceramides and S1P are controlled by enzymes involved in sphingolipid metabolism, including glucosylcerebrosidase (Gcase) and sphingosine kinase (Sphk). Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of enzymes involved in sphingolipid metabolism; preclinically, BXQ-350 was investigated in different in vitro and in vivo models. Clinically, BXQ-350 was investigated in a first-in-human Phase 1 safety dose and escalation study in cancer patients with recurrent advanced solid malignancies (NCT02859857). Results: Preclinical results demonstrated that BXQ-350 allosterically activates Gcase in vitro, in cells and in vivo in a significant and dose-dependent manner; as expected, in vivo, Gcase activation results in lower levels of glucosylceramides, as much as 2/3 lower for picomolar concentrations of BXQ-350. An increase in ceramides and a decrease in S1P are also observed. By impacting glucosylceramides, ceramides and S1P, BXQ-350 rebalances the S1P/ceramide rheostat in favor of an antitumoral state and homeostasis. By lowering S1P and glucosylceramides, BXQ-350 modulates the innate and adaptive immune response and repolarizes macrophages towards the antitumoral M1 phenotype, inhibits differentiation and activity of immunosuppressor of MDSCs, and promotes the proliferation of CD4+ and CD8+ Tcells as well as their activity. Clinical results showed BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS &amp;gt; 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms. Conclusions: Preclinical and clinical results demonstrated that BXQ-350 activates Gcase and modulates sphingolipid metabolism leading to a novel anticancer MOA that had not been clinically tested. Additional studies are ongoing to further elucidate BXQ-350’s MOA. Citation Format: Gilles H. Tapolsky, Charlie Cruze, Robin Furnish, Michael Gazda, Timothy Stephens, Lexy Stamper, Nikhil Wilkins, Ray Takigiku. BXQ-350: A novel biologic that allosterically activates glucosylcerebrosidase and demonstrates signs of activity in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3072.

Clinical meaning of sarcopenia in patients undergoing endoscopic treatment.

With increasing global life expectancy, the significance of geriatric assessment parameters has increased. Sarcopenia is a crucial assessment parameter and is defined as the age-related loss of muscle mass and strength. Sarcopenia is widely acknowledged as a risk factor for postoperative complications in diverse advanced malignancies and has a detrimental effect on the long-term prognosis. While most studies have primarily concentrated on the correlation between sarcopenia and advanced cancer, more recent investigations have focused on the relationship between sarcopenia and early-stage cancer. Endoscopic submucosal dissection (ESD), which is less invasive than surgical intervention, is extensively employed in the management of early-stage cancer, although it is associated with complications such as bleeding and perforation. In recent years, several reports have revealed the adverse consequences of sarcopenia in patients with early-stage cancer undergoing ESD. This literature review briefly summarizes the recent studies on the association between sarcopenia and ESD.

Radical Oophorectomy for Advanced Ovarian Cancer: A Feasibility Study from Tertiary Care Cancer Centre in Eastern India.

Radical oophorectomy was first performed by Hudson in order to remove an "intact ovarian tumour lodged in the pelvis, with the entire peritoneum remaining attached". We report 16 cases of radical oophorectomy done at our institute in the past 3years and have analysed the perioperative morbidity as well as feasibility of performing the surgery without much of perioperative complication. Twenty-three patients with advanced ovarian cancer who underwent modified en bloc pelvic resection at our institute, between November 2018 and October 2021, were initially enrolled. Patients below 70years, resectable disease on CT scan and no significant comorbidities were included. Exclusion criteria were extra-abdominal metastasis, secondary cancers or complete intestinal obstruction. Initially, 23 patients were enrolled out of which seven patients were excluded. Hence, a total of 16 patients with ovarian cancer extensively infiltrating into nearby pelvic organs and peritoneum were included. In Type 1 radical oophorectomy, retrograde modified radical hysterectomy alongwith in toto removal of the bilateral adnexae, pelvic cul-de-sac and affected pelvic peritoneum is done. Type 2 radical oophorectomy includes total parietal and visceral pelvic peritonectomy as well as an en bloc resection of the rectosigmoid colon below the peritoneal reflection. Radical oophorectomy is feasible with acceptable complication rate. In our study, only one patient had burst abdomen that too due to the poor nutritional status of the patient. There was no surgery-related deaths, but one patient succumbed to pulmonary embolism 5 days after the operation. Hence, radical oophorectomy proves to be an effective, feasible and secure surgical technique in cases of advanced ovarian malignancies with extensive involvement of peritoneum, pelvis and visceras.

Phase 1b study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis

Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced Tcell activation and anti-tumor immunity. In this phase 1b study, registered at Clinical. gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2weeks and i.p. ipilimumab every 6weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The trial enrolled 23 patients: 18 with ovarian cancer, 2 with uterine cancer, and 3 with cervical cancer. Study evaluable patients (n= 16) received a median of 2 prior lines of therapy (range: 1-8). Partial response was observed in 2 patients (12.5%; 1 ovarian, 1 uterine), and complete response was observed in 1 patient (6.3%) with cervical cancer, for an ORR of 18.8% (95% confidence interval: 4.0%-45.6%). The median duration of response was 14.8months (range: 4.1-20.8), with one complete response ongoing. Median PFS and OS were 2.7months and not reached, respectively. Grade 3 or higher immune-related adverse events occurred in 2 (8.7%) patients. i.p. administration of dual ICB is safe and demonstrated durable responses in a subset of patients with advanced gynecologic malignancy. The RP2D is 3mg/kg i.p. nivolumab every 2weeks plus 1mg/kg ipilimumab every 6weeks. This work was funded by Bristol Myers Squibb (CA209-9C7), an MD Anderson Cancer Center Support Grant (CA016672), the Ovarian Cancer Moon Shots Program, the Emerson Collective Fund, and a T32 training grant (CA101642).