Given the poor prognosis of advanced breast cancer, novel therapeutic approaches are needed to improve survival. Reliable, predictive laboratory assessments to monitor breast cancer progression or various specific conventional and experimental treatment regimens are not available.  Given the fact that limits have been reached in optimizing schedules and dosing of currently available chemotherapeutic or hormonal agents (e.g. dose dense treatment), another avenue that has promise is immunotherapy. Although it is agreed that in principle, all cancers including breast cancers are amenable to immunotherapeutic approaches such as vaccination to stimulate autologous cell-mediated host immune responses, basic knowledge regarding strategies to achieve this goal is very limited.  Dendritic cell (DC)-based breast cancer vaccines have received increasing attention and are currently being pursued by both the biotech/pharmaceutical industry as well as by academic researchers.  The current clinical trial is proposing to investigate the feasibility of using the universal tumor antigen oncofetal antigen/immature laminin receptor protein (OFA/iLRP) in a dendritic cell based vaccine protocol. It is designed to examine the inherent immune response in breast cancer patients directed towards OFA/iLRP and whether this immune response could be amplified and modified through actively vaccinating using autologous OFA/iLRP-pulsed dendritic cells reinjected into cancer patients.

OFA/iLRP is a logical target for immunotherapy because it has been found to be expressed in all human, as well as, murine cancers examined so far, which includes myeloid and lymphoid leukemias, lymphomas, renal cell carcinomas, prostate cancer, breast cancer, lung cancer, melanoma, squamous cell carcinoma, and ovarian cancer. It is not found on normal tissue after mid-gestation in fetal development. The 37 kDa OFA/iLRP is a highly conserved protein in humans, rodents, and other species. The 37 kDa OFA/iLRP upon binding laminin in the extracellular matrix induces secretion of metallproteinases which digest the collagen in extracellular matrix.  This process is important in tumor cell invasiveness, metastasis, and growth. It has also been demonstrated that OFA/iLRP is essential to embryo cell invasiveness in normal embryo-fetal development and is matured after organogenesis into a non-immunogenic, dimeric 67 kDA mature laminin receptor protein. However, soon after transformation, cancer cells re-express the auto-immunogenic, 37 kDa OFA/iLRP form. That OFA/iLRP is not just a tumor marker, but is an immunogen that has been shown through experimental immunization of inbred mice with OFA/iLRP to result in dose-dependent induction of OFA/iLRP-specific cytotoxic T cells capable of killing syngeneic tumor cells. Similarly, immunization with syngeneic dendritic cells transfected with OFA/iLRP  mRNA at weekly intervals induces significant anti-tumor immunity (67% of the mice are able to reject a lethal dose of A20 lymphoma cells). Also, OFA/iLRP-specific memory Th1 and cytotoxic T cells are clonable from the spleens of long-term survivors of x-irradiation induced lymphomagenesis in RFM strain mice without any experimental manipulation whereas, age-matched non-irradiated controls have no memory T cells specific for OFA/iLRP. 

OFA/iLRP is immunogenic in humans also.  In vitro stimulation of PBMC from breast carcinoma patients with autologous x-irradiated breast carcinoma cells generates CD4 and CD8 OFA/iLRP-specific T cell clones which are capable of killing the autologous tumor cells. Approximately 32% of the autologous tumor-reactive T cell clones were specific for OFA/iLRP.   In a recent collaborative study between our group and the Zeiss group in Germany, OFA/iLRP was shown to be expressed in a number of hematologic cancer lines, but not in normal human monocytes, DCs, and T cells from healthy individuals.  In vitro stimulation of naïve T cells from healthy volunteers with  autologous DCs which have been transfected with tumor RNA induced OFA/iLRP-specific cytotoxic T lymphocytes capable of specific killing of AML and CLL blasts, but showed no killing of OFA/iLRP-negative, diploid CD34 progenitor cells, bone marrow cells, normal B lymphoblasts, and dendritic cells.  

      By producing dendritic cells from breast cancer patient’s blood monocytes, loading them with OFA/iLRP, and inducing their maturation with cytokines, we will have produced an OFA/iLRP-specific autologous cellular therapy for the treatment of metastatic breast carcinoma.  The mechanism of action of the OFA/iLRP-loaded, autologous, mature, monocyte-derived dendritic cells (moDCs) is that of an active immunotherapy to generate a cancer-specific immune T cell response that will fight the patient’s cancer.  The OFA/iLRP-loaded mature, moDCs do not have a direct cytotoxic effect.  Instead, the anti-tumor effect is generated by the presentation of OFA/iLRP and activation of effector T lymphocytes specific for OFA/iLRP, which are present in the breast cancer patient’s blood and lymph. The activated OFA/iLRP-specific T cells then mount an attack against the breast carcinoma cells (which are OFA/iLRP-expressing).  This mechanism of action is unlike chemotherapeutic drugs that directly kill the tumor cells.  It is also different from immunotherapies that generically stimulate the immune response, such as IL-2, or specifically target the tumor via an anti-tumor antibody (herceptin).  Because the product requires the development of an immune response after administration, there is some delay in the potential effect of the product; the generation of the immune response and a clinical effect of that immune response may take several weeks.