The Need for Development of Therapeutic Breast Cancer Vaccine

Breast cancer (BC) is the most commonly diagnosed malignancy and is the second leading cause of cancer related deaths in American women. Currently there are no FDA approved vaccines for breast cancer. For this reason development of a therapeutic breast cancer vaccine is an area of research that needs urgent attention offering these women a better chance of a cancer free life. Many therapeutic vaccine strategies are under clinical trials for breast and other types of cancers [2]. Most vaccines being studied today, such as the gene transfer based vaccines require live cultured cells, which is time consuming and difficult to establish in many cancers. It is well known that breast cancer cells do not grow easily in vitro, significantly limiting the number of patients eligible for such clinical trials and ultimately vaccine therapy. A recent clinical trial evaluating vaccine-based therapy concluded that one of the major problems with gene-based cancer vaccine therapy is the delay vaccine production which significantly limits the access of patients to the trial and subsequent therapy [3]. Another potential problem is that the delay in vaccine production and subsequent administration could also result in a delay in treatment and progression of tumor metastasis resulting in increasing tumor burden and worsening prognosis. Therefore an optimum cancer vaccine requires a rapid production time, ease of delivery, and has the ability to be customizable for individual patients. Our proposed microparticle-based vaccine approach, addresses many of the problems associated with the current vaccine therapies including the high vaccine costs. We have developed a novel formulation using sustained release polymers encapsulating antigens in a biodegradable matrix containing immune potentiator adjuvants [4-7] . This has been confirmed in several other studies in our laboratory with ovarian [8], prostate [5] and melanoma [6] vaccines. Thus, we expect our proposed breast cancer vaccine formulations to be very robust for inducing immunity and to overcome most of the problems associated with soluble antigens.

We use a multi-fold approach to enhance the immunogenicity and efficacy of cancer vaccine microparticles. Particle-based vaccination for BC: There are several challenges in developing an effective vaccine, which include the maintenance of vaccine integrity and stability, avoidance of immune tolerance, and induction of strong protective immunity. We have been studying the encapsulation of drugs in our lab as well for the past 22 years and have shown that microparticles containing different drugs in the 0.5-2 µm size are readily taken up by phagocytic macrophages [9]. Recently, we have made major advances in the formulation process, and have several patents demonstrating the production of microparticles using a modified spray drying methodology in a single step process (US6555110, US7105158, US7425543). The microparticles provide a depot from which the antigens are slowly released and cause a long lasting immune response. These microparticles protect the antigen from being cleared out from the body thus, enhancing the vaccine stability. This will be a major advantage from the standpoint of advancing the vaccine formulation from bench to clinic as scale-up of the process can easily be achieved with no further modifications.

Adjuvant for immune-potentiation in BC: In the recent years, adjuvants like MF59 have been incorporated in vaccine formulation to enhance the specific immune response generated by the antigen. MF59 can potentiate the immune response by either increasing the antibody response and inducing cell mediated immunity i.e. they have a balanced strong Th1 / Th2 stimulation. The use of adjuvants not only enhances immunogenicity but could also permits the reduction in the antigen dose to be delivered in vaccine thus sparing the antigen. MF59 is a squalene in water emulsion which is commercially been approved in Europe with more than 27 million doses of vaccine containing MF59 have been administered. Novartis Vaccines has developed an influenza vaccine using MF59 along with inactivated, subunit seasonal prophylactic vaccine that is commercialized successfully as Fluad® in Europe. The safety and efficacy of MF59 has been established clinically with a large database [10].

Temporary depletion of Treg cells: Using a low dose of cyclophosphamide the Treg can be suppressed before vaccination. The dose of cyclophosphamide is much lower than the chemotherapeutic dose, thus there are no potential side effects to the patients. The Treg cells remain depleted for a short period of 45 days and then again reach normal levels. Thus during the vaccination regimen the Treg levels are low and aid in generation of a strong immune response [1]. In the present study, we have reported the efficacy of a transdermal metastatic breast cancer vaccine formulations which was evaluated in-vivo in mouse tumor model, using the 4T1 murine breast cancer cell line as a solid tumor model.