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News Archive: Michigan Oncology Journal Summer 98

Adoptive Immunotherapy

-Alfred E. Chang, M.D.,
Chief, Division of Surgical Oncology,
Director, Gene Therapy Program


Introduction
Adoptive immunotherapy is traditionally defined as the passive transfer of immunologically competent tumor-reactive cells into the tumor-bearing host to, directly or indirectly, mediate tumor regression. The feasibility of adoptive immunotherapy of cancer is based on two fundamental observations derived from extensive experimental animal studies. The first of these observations is that tumor cells express unique antigens that can elicit an immune response within the syngeneic host. The other is that the immune rejection of established tumors can be mediated by the adoptive transfer of appropriately sensitized lymphoid cells. Recognizing these fundamental principles required the establishment of animal models consisting of inbred strains of rodents and syngeneic transplantable tumors to eliminate the confounding influences of allograft transplantation immunity observed in earlier studies of tumor rejection in non-inbred animals. From these animal models, several principles have been established. These principles are summarized in Table 1.

Requirements for Clinical Therapy
As previously indicated, large numbers of immune cells are required to mediate the regression of an established tumor. However, unlike experimental animal systems, humans do not have readily available genetically identical counterparts to obtain immune cells. Therefore, tumor-reactive lymphoid cells will have to be identified and isolated from the patient with cancer. Furthermore, to generate sufficient quantities of immune cells, in vitro methods of expanding these cells while maintaining their immunological reactivities are required to render clinical therapy feasible. These represent formidable obstacles.

The requirements for successful adoptive immunotherapy in humans is summarized in Table 2. The ability to retrieve tumor-sensitized cells from the total pool of lymphoid cells available in the patient is of foremost importance. Human cancers spontaneously arise and may not be sufficiently immunogenic to allow the isolation of immune T cells. There are three potential sources to retrieve lymphoid cells for possible isolation of immune cells in humans which consist of: 1) peripheral blood, 2) lymph nodes or 3) tumor. The frequency of tumor-reactive lymphoid cells in the peripheral blood is exceedingly low. Hence, we and other investigators have been interested in isolating immune T cells from either a growing tumor (a.k.a. Tumor-Infiltrating Lymphocytes, TIL) or from lymph nodes draining sites of tumor vaccination (a.k.a. Vaccine-Primed Lymph Node cells, VPLN). We have developed methods to culture these T cells ex vivo in large quantities for subsequent infusion for adoptive immunotherapy in humans. We are currently performing several clinical trials to evaluate these approaches, which are briefly summarized in the next sections.

VPLN Cells Primed by Autologous Tumor plus BCG
In extensive animal studies, we have demonstrated that we can sensitize T cells to a non-immunogenic tumor by vaccinating the host with irradiated tumor cells mixed with a bacterial adjuvant (1). These VPLN can be surgically retrieved and expanded ex vivo using an antibody to T cells (i.e., anti-CD3) along with Interleukin -2 (IL-2). These cells are highly effective in mediating the regression of advanced tumors in mice. The bacterial adjuvant is important to “boost” the immune response to weak tumor antigens. We have translated these findings into a clinical protocol.

In this protocol, patients are vaccinated with irradiated tumor cells mixed with the bacterial agent, BCG. The tumor cells have been previously retrieved from the patient and should express all the tumor-associated antigens unique to that individual patient. The vaccine is inoculated intradermally and approximately one week later the VPLN cells are harvested in a minor outpatient procedure. In preliminary studies we have performed, the VPLN cells exhibit a significant degree of specific tumor-reactivity as measured in in vitro assays. For example, when these VPLN cells are exposed to autologous tumor cells in vitro, they secrete significant quantities of interferon-gamma, an important cytokine involved in the tumor rejection response (2,3). By contrast, these VPLN cells do not react to tumor cells from other patients (Figure 1).

The VPLN cells are expanded in large quantities ex vivo and are subsequently transferred back to patients intravenously along with the concomitant administration of IL-2. To date, we have seen signif-icant responses in several patients with renal cell cancer (Figure 2). We are currently conducting these trials in patients with advanced renal cell cancers, sarcomas, and head and neck cancers.

VPLN Cells Primed by Genetically Engineered Tumor Cells
More recent approaches for making tumor cells more immunogenic have been to genetically modify the cells to elaborate cytokines or express foreign antigens. In our laboratory, we have found that the engineering of tumor cells to secrete GM-CSF has dramatically enhanced their immune properties as a vaccine (4). Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a cytokine that recruits and promotes the proliferation of dendritic cells at sites where cytokine-secreting tumor cells are inoculated. This is thought to be important since dendritic cells are key to processing and presenting antigen to T cells.

In a clinical trial, we are genetically modifying tumor cells to secrete GM-CSF using a retroviral vector. These cells are then irradiated and inoculated intradermally as a vaccine to prime draining lymph nodes. One week later, the VPLN are retrieved using a blue dye technique to identify the immediate draining lymph nodes (Figure 3). The VPLN cells are expanded in a similar fashion to what we described earlier and subsequently transferred intravenously into patients. A patient with a complete clinical response is illustrated in Figure 4. This protocol is being performed in patients with stage IV melanoma.

TIL Derived from Genetically Modified Tumors
The University of Michigan has pioneered the applications of direct gene transfer into tumors using non-viral vectors (5). In patients with recurrent melanoma tumors, we have performed intralesional injections of therapeutic genes complexed with liposomes. The gene encodes for a foreign major histocompatibility complex (MHC) class I protein, which is taken up by tumor cells and causes them to express this foreign protein. We hypothesize that the expression of the foreign protein by the tumor cells induces a brisk inflammatory response within the tumor leading to augmented immune responses to tumor-associated antigens. In our analysis of this gene transfer approach, we have compared the cytolytic activity of TIL retrieved from the patients before and after gene injections and have found enhanced TIL reactivity due to the injections (Figure 5). In some patients, we have documented the regression of the injected tumor nodules. In our current studies, we are taking the TIL from patients after intralesional gene injections and using them for adoptive immunotherapy of residual disease. This study is for patients with stage IV melanoma.

In summary, the experimental observations that appropriately activated lymphoid cells can mediate regression of established tumor has led to the institution of clinical trials with encouraging results. Despite this limited success, further elucidation of the principles involved in sensitizing T cells to tumor antigens will allow broader applications of this therapeutic modality.

References

  1. Geiger JD, Wagner PD, Cameron MJ, Shu S, Chang AE. Generation of T cells reactive to the poorly immunogenic B16-BL6 melanoma with efficacy in the treatment of spontaneous metastases. J Immunother. 13:153-165, 1993.
  2. Chang AE, Aruga A, Cameron MJ, Sondak VK, Normolle DP, Fox BA, Shu S. Adoptive immunotherapy with vaccine-primed lymph node cells secondarily activated with anti-CD3 and Interleukin-2. J Clin Oncol. 15:796-807, 1997.
  3. Aruga A, Aruga E, Tanigawa K, Bishop DK, Sondak VK, Chang AE. Type 1 versus type 2 cytokine release by Vß T cell subpopulations determines in vivo antitumor reactivity. J Immunol. 159:664-673, 1997.
  4. Arca MJ, Krauss JC, Aruga A, Cameron MJ, Shu S, Chang AE. Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor. Cancer Gene Ther. 3:39-47, 1996.
  5. Nabel GJ, Gordon D, Bishop DK, Nickoloff BJ, Yang Z-Y, Aruga A, Cameron MJ, Nabel EG, Chang AE. Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA-liposome complexes. Proc Natl Acad Sci USA. 93:15388-15393, 1996.

 

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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.