Targeting the CBLB Immune Blocker in Cytotoxic T and NK Cells for Boosting Immunotherapy Against Kidney Cancers
Abstract
Describe the background and scientific objective or hypothesis for the proposed project: Kidney cancer is among the ten most common cancers in both men and women. Many patients with advanced kidney cancers eventually will have a recurrence, although often with the loss of chemo-sensitivity, and succumb to the disease. However, effective treatment options for advanced kidney cancers are still limited currently. Therefore, there is an unmet yet urgent clinical need to establish new therapy for overcoming kidney cancer. Although the development of the blockades of immune checkpoints has led to a paradigm shift for cancer therapy, a majority of patients with hard-to-treat cancers such as kidney cancers may not respond to these checkpoint blockades, probably due to certain immune obstacles. The hypothesis for this project is that an immune-suppressor (called CBLB) is a key target for developing specific inhibitors for boosting tumor immunotherapy because of the overwhelming evidence supporting the role of CBLB in immune suppression. Our team showed that a peptide CBLB inhibitor boosted anti-infectious immunity. The objective of this project is to address the problem of frequent ineffectiveness in repressing kidney cancer progression after initial immunotherapy and acquired immunotherapy resistance, a central problem in kidney tumor immunotherapy, by developing and employing novel drugs blocking the CBLB pathway in the tumor-killing immune cells to significantly improve the eradication of kidney cancer and prevent the development of immunotherapy-resistant kidney cancer in the long term. We focus on two specific aims: (1) identify small-molecule (or other agent) drugs that inhibit CBLB activity in the tumor-killing immune cells, and validate anti-CBLB inhibitors in activating the tumor-killing immune cells in vitro and stopping tumor growth in the kidney tumor mouse model, and (2) assess optimally combined regimens containing an anti-CBLB inhibitor and an immune checkpoint blockade (such as an anti-PD-1 blockade) in blocking tumor growth in the syngeneic mouse kidney tumor model. State an important gap in kidney cancer research or patient care on which the study will focus: This project will focus on overcoming an important gap, the problem of frequent ineffectiveness in repressing kidney cancer progression after initial immunotherapy and acquired immunotherapy resistance, which is certainly an important gap in kidney cancer research or patient care. The anticipated outcomes from the project will produce innovative therapeutic drugs, anti-CBLB inhibitors, or combination regimens with anti-CBLB inhibitors plus immune-checkpoint blockades to successfully boost the immunotherapy for kidney cancers and prevent the development of immunotherapy-resistant kidney cancer. Describe the innovative aspects of the proposed research project: This new therapy for patients with kidney cancer is innovative because this approach has been underexplored in kidney cancer. Innovative advantages are: (1) novel therapeutic targets in enhancing antitumor immune responses for kidney cancer, (2) mechanism of action distinct from prior art, and (3) intellectual property. Describe the impact that the proposed research project results might have on the field of kidney cancer research and/or patient care: The potential short-term impact of our project is to achieve the objective of the proposed specific aims by taking a two-pronged approach to identify novel anti-CBLB inhibitors and establish the in vivo effect of the candidate anti-CBLB inhibitors on suppressing kidney tumor progression in the syngeneic mouse model, and to study the efficacy of combination therapies with anti-CBLB inhibitors plus anti-PD-1 blockades for optimizing kidney cancer immunotherapies. The potential risk of this novel therapeutic drug will be limited because this therapy has low or rather limited toxicity to normal tissues. The potential long-term im
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010883
Entities
People
- Mickey C.‐T. Hu
Organizations
- Panorama Research (United States)
- United States Army