Safety and Efficacy Study of HER2/Neu (E75) Vaccine in Breast Cancer

The objectives of this study are the following: To assess safety and document local and systemic toxicity to the peptide vaccine (E75) in node-negative breast cancer patients. To determine the optimal dose of the immunoadjuvant, GM-CSF, necessary to elicit an in vivo cellular immune response to the peptide vaccine yet limit toxicity. To determine the optimal inoculation schedule to elicit an in vivo cellular immune response to the peptide vaccine. To correlate the efficiency of eliciting an in vivo cellular immune response to the peptide vaccine with the degree of HER2/neu expression in the patient's tumor.

Breast cancer is the most common malignancy and second most common cause of cancer-specific death among women in the United States. Despite advances in the diagnosis and treatment of breast cancer, one third of the women who develop the disease will die of the disease, accounting for approximately 46,300 deaths/year. While good primary therapies are available to treat early stage breast cancer, there is a substantial failure rate to these therapies in more advanced disease. Advances in the understanding of the immune response to cancer have led to the genesis of immunotherapeutic approaches. Specifically, the development of anti-cancer vaccines holds promise as an adjuvant and preventive therapy for patients after primary surgical and medical treatment for breast cancer, but who are at a high risk for recurrence. While patients with hormone receptor positive tumors have the option to undergo hormonal therapy, recurrence is especially high among estrogen receptor/progesterone receptor (ER/PR) negative patients. For these patients, currently there is no good treatment option after completion of primary therapy; close surveillance and watchful waiting is the standard. It is this population of patients that we have targeted with a vaccine strategy to induce cellular immunity. In our first vaccine study, (WU # 00-2005: Phase Ib Trial of HER2/neu Peptide (E75) Vaccine in Breast Cancer Patients at High Risk for Recurrence after Surgical and Medical Therapies) we have vaccinated node-positive, HER2/neu-positive breast cancer patients with an immunogenic peptide from the HER2/neu protein mixed with a FDA-approved immunoadjuvant, GM-CSF. The study is still enrolling patients, but to date the vaccine has been safe with very limited toxicity and has been very effective at inducing an immune response to the vaccinated peptide. However, it is too early to determine if this immunity will be protective against disease recurrence. However, with the early immunologic success of the trial, we now intend to more thoroughly study the optimal dose and schedule of vaccinations necessary to efficiently raise immunity against the peptide. In order to study these permeations, we will need to vaccinate significantly more patients; therefore, we propose to vaccinate node-negative breast patients since 75-80% of patients present with early stage breast cancer. Furthermore, we intend to vaccinate patients regardless of their HER2/neu status in order to determine the impact of prior exposure to this antigen on our ability to raise immunity against HER2/neu. Are patients with prior exposure to HER2/neu sensitized or tolerized to this antigen? This question must be answered in order to determine the usefulness of this vaccine as truly preventive in a cancer-naïve population.

HLA-A2- and HLA-A3- patients are prospectively followed for disease recurrence. Control patients are not vaccinated.

The 1 ml by volume vaccine is administered intradermally in 0.5 ml inoculums at two different sites within 5 cm of each other on an extremity. Vaccinations will be given according to the schedule the patient has been assigned and will be administered in the same lymph node draining area (same arm or thigh). In addition, an optional booster inoculation as requested by previously vaccinated patients will be offered every 6 months for the duration of the protocol. The dose will be determined by the PI based on the patient's response to the initial vaccination series.

The primary endpoints are the safety and optimal dosing of the vaccine to induce an in vivo peptide-specific immune response.

Time period needed to determine the maximum tolerated and optimal biologic doses (30 days after each monthly dose)

Inclusion Criteria: Breast cancer and negative lymph nodes HLA-A2+ and/or HLA-A3+ to receive the vaccine. HLA-A2-, HLA-A3- patients will be eligible to be included in the control group. Immunologically intact with a good performance status (defined below). Without evidence of disease. Patients may enroll while receiving appropriate hormonal therapy for their disease. Completion of all standard first-line therapies (but may still be on hormonal therapy) Exclusion Criteria: HLA-A2- and/or HLA-A3- patients will not be vaccinated Anergic by the Mantoux panel of recall antigens Receiving immunosuppressive therapy In poor health (Karnofsky <60%, ECOG >2) Tbili >1.5 mg/dL and creatinine>2 mg/dL Pregnancy (urine HCG) Active metastatic disease Involved in other experimental protocols (unless approval is first obtained by the other study PI) Refusal of standard therapies

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