Publications by authors named "K Totpal"
NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity.
Cancer Immunol Immunother
August 2024
Article Synopsis
- Cancer immunotherapy has transformed oncology, but immune responses are often suppressed in solid tumors, necessitating new strategies for enhancing immune activity.
- Researchers focused on the co-stimulatory receptor NKG2D, abundant on CD8+ tumor-infiltrating lymphocytes in breast cancer, to develop bispecific antibodies (HER2-CRB) that target both NKG2D and HER2.
- The HER2-CRB improved NK and T cell function, leading to increased antitumor activity when used with other antibodies, suggesting promising combinatorial potential for clinical trials.
An insufficient quantity of functional T cells is a likely factor limiting the clinical activity of T-cell bispecific antibodies, especially in solid tumor indications. We hypothesized that XmAb24306 (efbalropendekin alfa), a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein, may potentiate the activity of T-cell dependent (TDB) antibodies. The activation of human peripheral T cells by cevostamab, an anti-FcRH5/CD3 TDB, or anti-HER2/CD3 TDB resulted in the upregulation of the IL-2/15Rβ (CD122) receptor subunit in nearly all CD8+ and majority of CD4+ T cells, suggesting that TDB treatment may sensitize T cells to IL-15.
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- T cell-dependent bispecific antibodies (TDBs) not only target tumors but also cause systemic changes that can lead to adverse events in normal organs.
- In animal studies, there was a notable accumulation of lymphocytes and activation of endothelial cells in the liver, while tumor changes were less significant.
- The research suggests that specific genes, including CD9, play a role in enhancing T cell movement into normal tissues, potentially impacting the design of safer and more effective cancer immunotherapies.
New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair-deficient or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC.
View Article and Find Full Text PDFOvarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with ∼70% prevalence in the serous cancer subset.
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