We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.
Our study provides a largest registry-based analysis of survival outcomes in the TKI era. In majority of patients, the survival has improved significantly with the advent of TKIs as standard of care therapy. Survival for patients with non-clear cell RCC is clearly worse than clear-cell RCC and does not appear to have changed with TKIs. Elderly patients, women, and Black patients appear to have worse outcomes and these disparities merit further investigation.
Oligometastatic prostate cancer (OMPC), generally defined by presence of five or fewer metastatic sites on imaging, represents a transitional state between localized and widespread metastatic disease and encompasses a wide spectrum of disease biologies and clinical behaviors. A collaborative effort is ongoing to determine the genomics of OMPC. The prevalence of OMPC varies significantly in the literature and is likely to change further as substantial improvements in imaging improve our ability to reclassify a subset of patients with biochemical recurrence by conventional imaging as OMPC and another subset from OMPC to polymetastatic disease. The mainstay of OMPC treatment remains systemic therapy, either with androgen-deprivation therapy (ADT) alone or in combination with other agents (docetaxel, abiraterone, etc.). Focal therapies, including resection or radiotherapy (RT), to the primary tumor have demonstrated an improvement in outcomes, including failure-free survival in several retrospective studies. RT to the prostate has specifically demonstrated an overall survival (OS) advantage in patients with low-volume disease in a clinical trial. Improvement in outcomes has been observed with focal therapies for retroperitoneal and more distant metastatic sites in retrospective studies. Advancements in our understanding of the biology, imaging modalities, and treatments may allow for aggressive multimodality therapies in an effort to obtain deeper responses and, potentially, cures for selected patients with OMPC with favorable clinicopathologic characteristics. Participation in clinical trials or institutional registries is strongly encouraged for patients with OMPC who opt for an aggressive multimodality approach.
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