Cytokine Gene Transfer into Autologous Tumor Cells

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We have vaccinated a total of 16 patients with advanced melanomas in 2 successive phase I trials, one using autologous IL-7-gene-transduced tumor cells in 10 patients (110) and the other using IL-12-transduced tumor cells in 6 patients (111).

Figure 3 Rationale of cytokine gene transfer. Cytokine-gene transfer into tumor cells, causes a local secretion of cytokines (A) leading to an influx of immunological effector cells, such as T lymphocytes, NK cells, and DCs, and destruction of transduced tumor cells and inflammation (B). Destroyed tumor cells are taken up by antigen-presenting cells (APCs), which will migrate to the lymph node (LN) (C). After induction and expansion of tumor-specific T cells in the lymph node, tumor-reactive T cells of CD4-and CD8-phenotype will enter the circulation and destroy any (micro-) metastases detected at distant locations.

Figure 3 Rationale of cytokine gene transfer. Cytokine-gene transfer into tumor cells, causes a local secretion of cytokines (A) leading to an influx of immunological effector cells, such as T lymphocytes, NK cells, and DCs, and destruction of transduced tumor cells and inflammation (B). Destroyed tumor cells are taken up by antigen-presenting cells (APCs), which will migrate to the lymph node (LN) (C). After induction and expansion of tumor-specific T cells in the lymph node, tumor-reactive T cells of CD4-and CD8-phenotype will enter the circulation and destroy any (micro-) metastases detected at distant locations.

Immunizations were performed in weeks 1, 2, 3, and 6 by subcutaneous (s.c.) injection with total numbers of 5 x 106 to 3 x 107 modified tumor cells. In both trials, treatments were well tolerated and no major toxicity induced, except for mild fever and flulike symptoms in some patients vaccinated with IL-12-secreting tumor cells. Although no major clinical responses (complete remission: CR; and partial remission: PR) were achieved in any trial after the fourth vaccination, in IL-7-gene trial (110) 4 patients showed stable disease (SD) and 2 a mixed response (MR), whereas in IL-12 gene trial

(111), 3 patients showed stabilization of the disease with 2 still alive for 10 + months. One experienced a mixed response with regression of some cutaneous metastases over 3 months. An extensive immunological evaluation was performed after the fourth vaccination. In the IL-7 gene trial, 4 patients showed increased (NK) cell activity and 7 showing an increased lym-phokine activated killer (LAK) response upon vaccination

(112). In 3 of 7 patients evaluated, the frequency of blood tumor-reactive CTLp increased between 2.6- and 28-fold. Of interest, all patients showing increased CTL responses were confined to clinical responders: 2 with a mixed response and 1 with a SD, implying a role of CTL in controlling tumor growth. Moreover, the magnitude of T cell responses induced was highly associated with patient's Karnofsky index and DTH reaction before vaccination, suggesting that patients with minimal tumor load or minimal residual disease may preferentially benefit from such a vaccine (110). In the IL-12 gene trial (111), vaccination induced DTH reactivity against autologous tumor cells in 2 patients, with 1 showing a heavy infiltrate of CD4+ and CD8+ T cells in regressing metastasis. The frequency of blood tumor-reactive CTLp was increased (up to 15-fold) in 2 patients after immunization. Furthermore, an analysis of both cohorts of patients demonstrated a significant increase of unspecfic NK and LAK activitity in patien's peripheral blood after vaccination compared with preimmuniza-tion (112).

Palmer et al. (113) conducted a phase II trial to investigate the biological effect of an autologous IL-2-secreting tumor cell vaccine introduced by retroviral gene transfer in 12 melanoma patients. Patients were treated for 1, 2, or 3 times with 107 modified tumor cells. No complications were observed. Three patients had stable disease for 7 to 15 + months, 1 for 17 weeks, the latter developed antitumor DTH after the first vaccination. In 4 patients, including 3 with 7 to 15 + months disease stabilization, the CTL responses to autologous tumor cells were increased upon vaccination.

Groups from Vienna, Freiburg, and Wurzburg performed a phase I trial to evaluate the safety and tolerability of repeated skin injections of IL-2-transfected autologous melanoma cells into patients with advanced disease using a transferrin-me-diated and adenovirus-enhanced transfection system (114). Fifteen patients received 2 to 8 skin vaccinations of either 3 x 106 (intradermal) or 1 x 107 (half intradermal, half subcutaneous) transfected melanoma cells per vaccination (secreting 140 to 17,060 biological response modifier program units of IL-2/106 cells/24 h). Overall, the vaccine was well tolerated. All patients displayed modest local reactions (erythema, induration, and pruritus) and some experienced flulike symptoms. Apart from newly appearing (4 of 14) and increasing (5 of 14) antiadenovirus and newly detectable antinuclear antibody titers (1 of 15), recipients developed de novo or exhibited increased melanoma cell-specific delayed-type hyper-sensitivity (DTH) reactions (8 of 15) and vitiligo (3 of 15) and showed signs of tumor regression (3 of 15). None of the patients exhibited complete or partial regressions (114).

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