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Project

Delivery of Targeting Nano-Photo-Imiquimod to Enhance Response Rate of Advanced Bladder Cancer to Check Point Blockade Antibody Therapy

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 4.6 M
Funding amount
Abstract
PUBLIC ABSTRACT

Bladder cancer (BCa) is the fourth most common cancer among men and tenth most common cancer among women. Although non-muscle-invasive BCa was the focus of our previous Peer Reviewed Medical Research Program (PRMRP) project, it is the locally advanced and metastatic bladder cancers (the topic of this Expansion Award) that cause the vast majority of morbidities and mortality. We will leverage our experience and expertise gained from the previous PRMRP award on the preclinical development of porphyrin-based nancarrier (PLZ4-PNP) to develop a novel and more effective indocyanine green-based (ICG) nanocarrier (CPCI-NP) that can encapsulate imiquimod, a potent immunostimulant, to all tumor sites through intravenous administration. Because of the indocyanine green component, CPCI-NP can generate heat and reactive oxygen radicals when illuminated with light. As a result, illuminated tumor cells die and release tumor proteins to trigger the host to mount an immune response against the cancer. When the nanocarrier is loaded with imiquimod, a potent immunostimulant, the host immune response against the tumor is even stronger. We have found CPCI-NP to be highly effective against 4T1 mouse breast cancer model, particularly when the photo-immunotherapy was given in combination with anti-PD-1 checkpoint blockade antibody currently used in the clinic. Such triple therapy not only eradicated the light-illuminated primary tumors, but also dramatically inhibited the light-untreated distant tumors via systemic activation of anti-tumor immune response. We believe such novel photoimmunotherapy can be applied to BCa patients, even with tumors widely distributed. PLZ4, a peptide discovered in our laboratory, will be used to decorate our nanocarriers because it can guide the nanocarrier to all BCa sites when given intravenously.



Relevance to Topic Area: The proposed project fits well with the area of “Sustained-Release Drug Delivery.” Encapsulated imiquimod will be delivered effectively by the nanocarrier to all the BCa sites, where the immunostimulant will be sustained-released over a few days to a week, and induce systemic antitumor immune response, when given in conjunction with local phototherapy and systemic anti-PD-1 antibody therapy. Regarding “areas of encouragement,” although anti-infectious agent is not the focus of this project, nanoimiquimod could be useful as a potent component of anti-viral vaccine development.



Applicability and Impact of Research: The current proposed project will be focused on locally advanced and metastatic BCa. Locally advanced BCa is usually treated with neoadjuvant chemotherapy followed by bladder resection, which is associated with the worst health-related quality of life of all cancer types. As immunotherapy can induce durable response and even cure, a successful outcome of this proposed project can possibly spare those patients from this highly morbid treatment. The standard first-line treatment for metastatic BCa is combination chemotherapy with a response rate of 50%. The only U.S. Food and Drug Administration-approved second-line therapy is check point blockade immunotherapy, which has a response rate of approximately 20%. The current project, if successful, can greatly increase the response rate, e.g., to over 50%, of check point blockade immunotherapy, and significantly improve the clinical outcomes of locally advanced and metastatic BCa.



BCa is common in Veterans because most of them are elderly males with a history of smoking. Smoking is the single most important risk factor for BCa. According to the U.S. Department of Health and Human Services National Medical Expenditure Survey in 1987, 75% of Veterans had a history of smoking of at least 100 cigarettes. Of the smoking-related cancers, BCa has the highest prevalence, even higher than lung cancer (4.4 versus 2.9 per 1,000 Veteran population). The Department of Veterans Affairs (VA) is spending a lot of resources on the diagnosis, treatment, and follow-up of BCa. Co-Principal Investigator Dr. Pan is a Staff Oncologist for the VA Northern California Health Care System. Accomplishment of this project can be readily translated to the care of Veterans.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Clinical Research

  • RCDC

    Immunization

  • RCDC

    Prevention

  • RCDC

    Vaccine Related

  • HRCS HC

    Cancer

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science