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

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

Chinese origin rhesus macaque major histocompatibility complex class I molecules promiscuously present epitopes from SIV associated with molecules of Indian origin; implications for immunodominance and viral escape

The presentation of identical peptides by different major histocompatibility complex class I (MHC-I) molecules, termed promiscuity, is a controversial feature of T cell-mediated immunity to pathogens. The astounding diversity of MHC-I molecules in human populations, presumably to enable binding of equally diverse peptides, implies promiscuity would be a rare phenomenon. However, if it occurs, it would have important implications for immunity. We screened 77 animals for responses to peptides known to bind MHC-I molecules that were not expressed by these animals. Some cases of supposed promiscuity were determined to be the result of either non-identical optimal peptides or were simply not mapped to the correct MHC-I molecule in previous studies. Cases of promiscuity, however, were associated with alterations of immunodominance hierarchies, either in terms of the repertoire of peptides presented by the different MHC-I molecules or in the magnitude of the responses directed against the epitopes themselves. Specifically, we found that the Mamu-B*017:01-restricted peptides Vif HW8 and cRW9 were also presented by Mamu-A2*05:26 and targeted by an animal expressing that allele. We also found that the normally subdominant Mamu-A1*001:01 presented peptide Gag QI9 was also presented by Mamu-B*056:01. Both A2*05:26 and B*056:01 are molecules typically or exclusively expressed by animals of Chinese origin. These data clearly demonstrate that MHC-I epitope promiscuity, though rare, might have important implications for immunodominance and for the transmission of escape mutations, depending on the relative frequencies of the given alleles in a population