Current therapies fail to cure 40% of breast cancer patients, who relapse and die from drug-resistant disease. Immune-based therapies work differently than drugs that destroy tumor cells directly by recruiting the patient’s own immune system to seek out and kill tumor cells. Immune-based therapies are not limited by drug resistance, are highly specific, and typically have few side effects. Importantly, they uniquely result in a durable therapeutic impact due to memory. Immune-based therapy includes vaccines and antibodies. Vaccines activate long-lasting T cells that kill existing cancers, and can remember to kill tumors should they arise again. Antibodies target proteins such as HER-2 on cancer cells, and immune cells bind these antibodies to kill tumors. HerceptinR is a HER-2-specific antibody that significantly improves the survival of patients with early and metastatic HER-2hi breast cancer.
Because tumors arise from the patient’s own tissues, the immune system sees them as “self” rather than as dangerous invaders (like an infection). A special type of regulatory T cell (Treg) keeps the immune system from recognizing “self”, and prevents tumor immunity. Low doses of the chemotherapy drug cyclophosphamide (CY) can reduce Tregs in breast cancer patients, sparing the good T cells needed to fight cancer. HER-2-specific antibodies can supercharge our cell-based vaccine by forming a bridge between HER-2 on the vaccine cells and host dendritic cells. Antibody-supercharged dendritic cells generate more killer/memory T cells of higher quality than dendritic cells alone. Our ongoing analysis of T cells from patients treated with CY, Herceptin and vaccine suggests that the T cells are of higher quality. We continue to test this strategy in patients with HER-2lo metastatic breast cancer, where Herceptin does not fight breast cancer directly. We have enrolled about 65% of the planned 60 patients. Our integrated clinical studies will identify the most active combination vaccine regimen to test for preventing relapse patients with early breast cancer, regardless of HER-2 expression level.
Neuroblastoma is an aggressive cancer of the nervous system that primarily affects very young children. Half of the children affected by this disease are less than 18 months old. Neuroblastoma represents 8-10% of all childhood cancer cases, but 15% of all childhood cancer deaths, and over the past twenty years, the survival statistics have not improved, with only 40% of all affected children expected to have any hope of a long-term survival. Treatments for neuroblastoma are generally aggressive, and include multiple treatment types including surgery, radiation, chemotherapy, and hematopoietic progenitor cell (HPC) transplant (more often referred to as bone marrow transplant). It is this latter treatment type, HPC transplant, that was associated with the greatest improvement in survival when it was introduced for neuroblastoma treatment over 20 years ago, and which forms the foundation for this proposal. In treating neuroblastoma, the actual transplant is preceded by a regimen of very high dose chemo- and radiation-therapy. This reduces the patient’s tumor burden to the lowest possible level, but also wipes out the blood forming cells of the bone marrow. The HPC that are transplanted re-establish healthy bone marrow. In the process of marrow re-establishment, the patient’s immune system also re-establishes. It has been seen in animal models and in some clinical situations that a specific type of cells in the immune system, called lymphocytes, will preferentially recognize and respond to the agents in vaccines if those vaccines are administered early during this re-establishment process. Our goal in the proposed study will be to create vaccines from killed neuroblastoma cells taken from each patient, and then to administer those vaccines during recovery from HPC transplant. We will follow all patients in this study for an entire year to determine if this vaccine protocol produces immunity against the patient’s own neuroblastoma cells, and also if it results in tumor suppression. Autologous HPC transplant has been used in the treatment of neuroblastoma for over twenty years, but the success of this therapy has remained below 40 percent. Dendritic cell therapy has been tested in a very limited number of patients with some hint of promise. This study will be the first effort to combine these two approaches in a way that we expect to be synergistic. This unique study is being carried out as a collaborative effort between the Cell Therapies Facility of the MoffittCancerCenter and the Blood and Marrow Transplant Unit of All Children’s Hospital.
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