Fusion Proteins to Improve Immunotherapy
Abstract
Rationale: Cancer cells are adapted to be invisible to the immune system and are not attacked by the body s own defenses, thus tumors can grow and spread by a process called metastasis. Fortunately, new anti-cancer therapies, called immunotherapies, include drugs that remove the natural invisibility of cancer cells and allow our own immune system to attack and kill the cancer cells. One of these most promising new therapies is based on stopping cancer cells from cloaking themselves in proteins that usually cover our healthy immune cells. Two of the proteins involved are named programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). Laboratory studies show that when one or both of these proteins are inhibited, generally by antibodies, immune cells recognize and kill the cancer cells. Patients with melanoma, ccRCC (clear cell renal cell carcinoma) and NSCLC (non-small cell lung cancer), who are treated with PD-1 and PD-L1 antibodies, have reduced tumor growth and improved survival. Recently, PD-L1 therapies have also been shown to benefit advanced triple-negative breast cancer (TNBC) patients, in a study by Dr. Emens, a co-investigator on this proposed project. Despite the promise of PD-L1 in treating TNBC patients, only 19% respond to the treatment. What causes the low response rate? Most likely this is because immune cells cannot infiltrate tumors because of two problems: (i) protective "shields" created by the tumors, and (ii) suppression from tumors and from the immune system. A critical element in the immune evasion and therapy resistance mechanisms is a small protein called CXCL12. Increased levels of CXCL12 in the tumors contribute to resistance to immune, chemo-, and targeted therapy, and promote tumor growth and metastasis. Inhibition of CXCL12 results in more effective treatments, reduced tumor growth and metastasis, and improved immune response. Overarching Challenge: Prolonged inhibition of CXCL12 that affects the whole body is not ideal because: (i) CXCL12 is needed for essential physiological processes such as maintenance of adult bone marrow, and (ii) such inhibition may be toxic. Therefore, we propose agents that can selectively inhibit CXCL12 in the tumors. Objective: Our goal is to replace existing therapies for CXCL12 with ones that can selectively trap, inactivate, or even deplete CXCL12 from the tumors, and thereby improve treatment response. We hypothesize that new tumor-homing antibodies, armed with decoys, will inhibit PD-L1, and simultaneously trap or inactivate the CXCL12 in the tumors. Aims: To achieve our objective, we will pursue a number of individual and complementary aims. We will synthesize "immunotherapy sensitizing antibody conjugates (ISACs)." Our cell culture and mouse model studies will focus on understanding the immune system response, tumor growth, and metastasis following therapy with ISACs. Because all the materials we will use in the laboratory are clinically translatable, our observations can form a bridge between preclinical and clinical studies. To achieve tumor selectivity, we will use PD-L1 binding antibodies that have shown promise in TNBC patients. We will make decoys from fragments of CXCR4 that bind to CXCL12, but lack functional activity and are non-immunogenic. The agents we plan to develop are modular and generalizable with any breast cancer targeting antibodies. We can test our hypothesis in syngeneic and humanized mouse model systems. Our research will combine the expertise from laboratories specializing in breast cancer biology, bioconjugate chemistry, immunology, molecular imaging, and drug development. Clinical Applicability, Benefits, and Risks: The new immune therapy drugs that we will develop will be important new treatments for TNBC and should significantly increase the percentage of patients who respond to therapy (at present only 19% of patients respond to PD-L1 antibodies). This ultimate applicability is bas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610323
Entities
People
- Sridhar Nimmagadda
Organizations
- Johns Hopkins University
- United States Army