Abstract
Scientific Abstract
Although it has been well established experimentally that the transfer of sensitized T lymphocytes can mediate potent antitumor effects, extrapolating the principles of adoptive immunotherapy obtained from animal studies to clinical therapy will require the development of innovative techniques to isolate and propagate antitumor effector T cells from cancer patients. Toward this end, we have established culture methods whereby cells from tumor-draining or tumor primed lymph nodes (LN) can be sensitized to acquire therapeutic efficacy. Since these cells do not demonstrate overt antitumor reactivity before culture, they are functionally referred to as “pre-effector” cells. One method to generate antitumor effector T cells involves the sequential activation of pre-effector LN cells with anti-CD3 mAb followed by expansion in low concentrations of IL-2. Animal experiments have demonstrated that the antitumor reactivity of these anti-CD3/IL-2 activated cells are exquisitely tumor-specific and mediate the regression of established tumor in adoptive immunotherapy.
A major obstacle which confronts the clinical application of adoptive immunotherapy is the relatively weak immunogenicity of human cancers which hampers the induction of sensitized pre-effector cells. Recent observations in animal studies indicate the tumors can be genetically altered to enhance the host immune response against native or parental tumor antigens. We found that the transfection of the poorly immunogenic B16BL6 murine melanoma tumor with the GM-CSF gene resulted in the sensitization of immune lymphoid cells when inoculated into the syngeneic host. Draining LN cells removed from these animals and activated by the anti-CD3/IL-2 culture procedure generated potent therapeutic effector cells which mediated the adoptive immunotherapy or established metastatic parental tumors. More importantly, these activated cells were more potent in their therapeutic efficacy compared to similarly derived cells utilizing standard bacterial immune adjuvants. These observations provide the rationale for this clinical protocol to examine autologous tumor cells modified with the GM-CSF gene, which will be utilized as a vaccine to induce pre-effector LN cells in patients with advanced cancers. Human cancers have been postulated to be poorly immunogenic based upon their spontaneous origins. These vaccine-primed LN cells will be activated by the anti-CD3/IL-2 method and subsequently transferred intravenously to patients along with the concomitant administration of IL-2 (360,000 IU/kg q8h × 5 days) to support their survival/function in vivo.
The specific aims of the protocol are: 1) To assess the feasibility and toxicity of adoptive T cell immunotherapy of cancer with anti-CD3/IL-2 activated LN cells that are primed in vivo with GM-CSF modified autologous tumor cells, 2) To evaluate the antitumor efficacy and in vivo immunological reactivity of patients receiving adoptively transferred T cells, and 3) To investigate the in vitro immunological reactivities of the activated T cells that might correlate with their in vivo antitumor function.
NON-TECHNICAL ABSTRACT
This study involves the use of novel methods to treat patients with advanced cancer by manipulation of their immune system. Based on extensive animal studies, we know that the immune system has the potential to recognize tumor cells as being foreign to the body and destroy them. The critical component of the immune system which appears to be involved in the rejection of tumors are lymphocytes. The ability to generate these lymphocytes in the laboratory would be useful for potential therapy of cancer. This approach has been called adoptive immunotherapy and involves the infusion of cancer reactive lymphocytes into patients in order to cause tumor shrinkage.
Unfortunately, the generation of immune lymphocytes which can reject human cancers has been extremely difficult. One possible reason why this problem exists is that the foreign proteins present on human tumor cells are very weak in their ability to stimulate the immune system to react against them. Based on our animal studies, we have devised an approach to artificially stimulate immune cells that may be used for the treatment of human tumors that under normal circumstances would not occur. This involves a two-step process. The first step requires vaccination of the patient with their own tumor cells which have previously been removed and genetically engineered to secrete an immune factor called GM-CSF. The tumor cells are irradiated prior to injection into the skin in order to prevent outgrowth of tumor at the site. It has been found in animal studies that the production of GM-CSF by the gene-modified tumor cells promotes an immune response in lymph nodes near the vaccination site. Lymph nodes are small glands of the immune system where lymphocytes congregate. The lymph nodes adjacent to the vaccination sites will be surgically removed approximately 7 to 10 days later and taken to the laboratory for further processing. In the laboratory, cells from the lymph nodes will be stimulated and grown in special flasks by methods we have previously described for a 2 to 3 week period in order to generate a large number of immune lymphocytes. These lymphocytes will be collected and infused back into the patient along with the administration of interleukin-2, another immune protein. The interleukin-2 has been found to promote the antitumor effect of the immune lymphocytes in cancer patients.
This clinical study proposes to address several important questions. These questions include: 1) Can this clinical treatment program be performed as described and what are its side-effects, 2) What antitumor response can be seen with this treatment, and 3) What is the immunological function of the immune lymphocytes, as assessed by laboratory tests.
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