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Abstract

A prospective pilot study was performed in order to assess the safety of treating recurrent malignant gliomas (MGs) with locally infused autologous tumor infiltrating lymphocytes (TILs) and recombinant interleukin-2 (rIL-2). Six patients were entered between June 27, 1994 and June 2, 1995 and followed until July 1, 1998. At surgery an Ommaya reservoir was placed for later infusion of TILs and rIL-2. Following surgery, autologous TILs were expanded in vitro in the presence of rIL-2 and infused on treatment days 1 and 14, with concurrent rIL-2 infusions performed three times each week for one month. Following completion of immunotherapy all patients were offered chemotherapy. Phenotypic analysis demonstrated TILs to be T-lymphocytes (87-99% CD3+). Of these, 4 of 6 cases (67%) phenotyped as cytotoxic/suppressor T-lymphocytes (CD8+) and 2 of 6 cases (33%) phenotyped as helper/inducer T-lymphocytes (CD4+). TILs demonstrated limited selective cytotoxicity, with dose dependent cytotoxicity against autologous tumor, allogenic tumor and long term MG cell lines. There were no significant (Grade 3 or 4) complications. One patient developed transient low grade fevers, and 2 developed asymptomatic hydrocephalus. All patients developed transient and asymptomatic cerebral swelling, noted on the immediate post-treatment imaging studies. At three and six month follow-up, 3 patients responded with partial response, 2 demonstrated stable disease and 1 patient progressed. At long term follow-up, 1 patient had a complete response (45 month follow-up), 2 had a partial response (48 and 47 month follow-up) and 3 patients expired as a result of progressive disease (at 12, 12 and 18 months following immunotherapy). A relationship between subsequent chemotherapy or extent of resection to outcome was not apparent but could not be excluded. This pilot study demonstrated that locally infused autologous TILs and rIL-2 could be delivered without serious toxicity. Further studies are indicated to determine the safety and long term efficacy of TIL immunotherapy.

Immunotherapy for Primary Brain Tumors: No Longer a Matter of Privilege

“…In its earlier renditions, ALT included the transfer of a variety of immune populations, not just T-cells. These have included peripheral blood mononuclear cells (PBMC) (21); lymphokine/mitogen-activated killer cells (LAK) (22); tumor-infiltrating lymphocytes (TIL) (23); and cytotoxic T-lymphocytes (CTL) (24, 25), administered either systemically (preclinical data supports tumor trafficking (26)) or into the tumor cavity. Targets have varied, and newer renditions have combined ALT with active vaccination (27) and/or prior myelosuppressive regimens (28) (NCT00693095), in efforts to promote survival and functional expansion of the transferred cells in vivo (active trials: NCT0114427, NCT01801852).…”

Tumor-infiltrating lymphocytes (TILs) from patients with glioma

“…7 In total, 12 clinical trials were conducted using either LAK cells, or targeted T-cell therapies. [8][9][10][11][12][13][14][15][16][17][18] Quattrocci treated patients with gliomas with intra-lesional TIL and IL-2 19 leading to clinically relevant responses, i.e., one patient experienced a complete response, two patients a partial response and three patients progressed. Given the promising results from patients with melanoma and from patients with epithelial cancer, TIL therapy may also represent a viable option for the biological therapy of patients with glioma.…”

A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

“…In a pilot study exclusively performed to date against patients with recurrent malignant gliomas that were treated with intratumoral infusion of ex vivo expanded autologous TILs with IL-2, one of six patients showed complete remission, two had partial responses, and three died of tumor progression [56]. The cytotoxic activity of TILs against autologous tumors in vitro was variously dependent on the patients and was not correlated with the clinical outcome in this study.…”

“…Major therapeutic limitation of these cells against tumors is that their lytic properties are not specifically directed against tumor cells. Autologous tumor cells were usually used as antigen source in ACT using LAK cells for malignant gliomas [56–59]. …”