Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res

Abstract Despite advancements in the treatment of ovarian cancer, this disease continues to be a leading cause of cancer death in women. Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy for many cancers. We designed a chimeric receptor linking NKG2D, a natural killer (NK) cellactivating receptor, to the CD3Z chain of the T-cell receptor to target ovarian tumor cells. Engagement of chimeric NKG2D receptors (chNKG2D) with ligands for NKG2D, which are commonly expressed on tumor cells, leads to T-cell secretion of proinflammatory cytokines and tumor cytotoxicity. In this study, we show that >80% of primary human ovarian cancer samples expressed ligands for NKG2D on the cell surface. The tumor samples expressed MHC class I-related protein A, MICB, and UL-16 binding proteins 1 and 3. ChNKG2D-expressing T cells lysed ovarian cancer cell lines. We show that T cells from ovarian cancer patients that express chNKG2D secreted proinflammatory cytokines when cultured with autologous tumor cells. In addition, we show that chNKG2D T cells can be used therapeutically in a murine model of ovarian cancer. These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for ovarian cancer. [Cancer Res 2007;67(10):5003-8

Egg freezing for fertility preservation and family planning: a nationwide survey of US Obstetrics and Gynecology residents

Abstract Background Little is known about resident attitudes toward elective egg freezing (EF) or how educational exposure to EF affects residents’ views and ability to counsel patients. This study aimed to evaluate US OB/GYN residents’ views on elective EF, decisions regarding family planning, and whether education on EF affects these views and self-reported comfort discussing EF with patients. Methods A 32 question survey was emailed to program directors at all US residency programs for distribution to residents. Chi-square tests were used to evaluate the relationship between educational factors and views on EF and comfort counselling patients. Results Of those surveyed, 106 residents and 7 fellows completed the survey (103 female). Almost three quarters of female respondents reported postponing pregnancy due to residency (71.8%). Non-exclusive reasons for this choice included career plans (54.4%) and concern for childcare (51.5%) and for fellow residents and their program (50.5%). Of the male and female residents who reported educational exposure to EF (57.5%), almost all of them (95.4%) received this in an REI rotation. Only half of female residents reported being comfortable counseling a patient on EF (49.5%). For female residents, education on EF (p = 0.03) and more advanced level of residency (p = 0.02) were significantly associated with comfort counseling a patient on EF. Conclusions Female OB/GYN residents are choosing to delay pregnancy during residency for career and social support reasons. Few residents feel comfortable counseling patients on EF, but appropriate curricular content on EF during residency could improve residents’ comfort in assisting patients with reproductive planning

33 UPLIFT (ENGOT-ov67/GOG-3048) a pivotal cohort of upifitamab rilsodotin (XMT-1536; UpRi), a NaPi2b-directed antibody drug conjugate (ADC) in platinum-resistant ovarian cancer

Upifitamab rilsodotin (UpRi), is a first-in-class antibody drug conjugate targeting NaPi2b, a sodium-dependent phosphate transporter protein broadly expressed in solid tumors including high-grade serous epithelial ovarian, fallopian tube and primary peritoneal cancers (OC), and limited expression in healthy tissues. Preliminary antitumor activity from the Phase 1b expansion cohort of heavily pretreated patients with OC has been reported (Richardson et al., SGO 2022). Data through June 2021 demonstrated clinically meaningful activity in patients with recurrent ovarian cancer, with notable activity in patients with NaPi2b-high tumors (TPS ≥75) treated at the optimized dose of 36 mg/m2. Effective and well-tolerated treatments for platinum-resistant ovarian cancer (PROC) remain a substantial unmet medical need. Single agent chemotherapy, which is the standard of care, has limited efficacy (response rate ≤12%) and short duration of response. Based on the encouraging anti-tumor activity of UpRi, UPLIFT was designed to be a single-arm Phase 2 registrational trial for UpRi in PROC. The UPLIFT cohort is enrolling patients with platinum-resistant high grade serous ovarian, fallopian tube and primary peritoneal cancer with up to 4 prior lines of therapy. Prior bevacizumab is required for patients with 1 or 2 prior lines of therapy but is not required for patients with 3–4 prior lines of therapy. Patients may enroll regardless of NaPi2b expression; ≤ Grade 2 peripheral neuropathy is permitted. Primary platinum refractory patients are excluded. UPLIFT will enroll approximately 180 patients globally, including approximately 100 patients with high NaPi2b expression. UpRi will be dosed intravenously at 36 mg/ m2 up to a maximum dose of ~80 mg every 4 weeks. Baseline tumor samples (fresh or archived) will be collected for central analysis of NaPi2b expression. The primary endpoint is ORR in patients with high NaPi2b expression. The cut-off for high NaPi2b expression is Tumor Proportion Score (TPS) ≥75, which was based on data from the Phase 1 expansion cohort. Secondary endpoints include ORR in the overall population, duration of response, and safety. This study is being conducted in collaboration with ENGOT (ENGOT-ov67) and GOG (GOG-3048). Patients will be enrolled globally. NCT03319628 This is a Trial in Progress; therefore, we do not have results/conclusions at this time. This is a Trial in Progress; therefore, we do not have results/conclusions at this time

TP036/#426 Uplift (ENGOT-OV67/GOG-3048) a pivotal cohort of the XMT-1536–1 trial of upifitamab rilsodotin (XMT-1536; UPRI), a NAPI2B-directed antibody drug conjugate (ADC) in platinum-resistant ovarian cancer

ObjectivesUpRi is a first-in-class NaPi2b ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in healthy tissues. Interim data from the Phase 1b expansion cohort of heavily pretreated patients with recurrent HGSOC has been reported. These data demonstrated clinically meaningful activity, notably in patients with NaPi2b-high tumors (TPS≥75). Effective and well-tolerated treatments for PROC remains an unmet medical need. The standard of care, single-agent chemotherapy, has limited efficacy, significant toxicities, and short duration of response. UPLIFT was designed as a single-arm Ph2 registrational trial for UpRi monotherapy in PROC.MethodsUPLIFT is enrolling patients with PROC with up to 4 prior LoT. Prior bevacizumab is required for patients with 1–2 prior LoT only; it’s not required for patients with 3–4 prior LoT. Patients may enroll regardless of NaPi2b expression; ≤ Grade 2 peripheral neuropathy is permitted. Primary platinum refractory patients are excluded. UPLIFT will enroll ~180 patients globally, including ~100 patients with high NaPi2b expression. UpRi is dosed IV at 36 mg/m2 up to ~80 mg dose maximum Q4W. Baseline tumor samples (fresh or archived) will be collected for central analysis of NaPi2b expression. The primary endpoint is ORR in NaPi2b-high expressing patients. The cut-off for high NaPi2b expression is TPS≥75. Secondary endpoints include ORR in the overall population, duration of response, and safety. UPLIFT is conducted in collaboration with ENGOT (ENGOT-ov67) and GOG (GOG-3048). NCT03319628Results trialinprogressConclusions trialinprogres