Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma

Abstract

Background. The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin‐2(IL‐2) plus lymphokine‐activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. Methods. Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL‐2 after reoperation. Lymphokine‐activated killer cells and IL‐2 were given on day 1, and IL‐2 alone was given 5 times during a 2‐week cycle. This cycle was repeated at 2 weeks to constitute one 6‐week course of therapy. Each two‐cycle course of treatment was repeated at 3‐month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. Results. The maximal tolerated dose for a 12‐dose course of therapy was 1.2 million international units (MIU) per dose. Dose‐limiting, cumulative IL‐2‐related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 → 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 ± 3.7 weeks), with 1/18 alive at 1 year (>6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. Conclusions. Lymphokine‐activated killer cells and IL‐2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted. Cancer 1995; 76:840–52.

NK cell-based immunotherapy for malignant diseases

“…88 More success was attained when adoptively transferring IL-2-activated LAK cells rather than administering IL-2 systemically. [89][90][91] Combining IL-2 and IFN-a with GM-CSF has been shown to be effective, providing a solid basis for using IL-2 to stimulate antitumor activity from endogenous NK cells. 60 Other NK cell activators, such as IL-12, IL-15, IL-18 and IL-21, have been successfully tested in preclinical cancer models as part of various vaccination strategies.…”

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.…”

Immunotherapy for Glioblastoma

“…Furthermore, the median survival was 53 weeks following re-operation compared to 25.5 weeks for contemporary patients with GBM who underwent re-operation and chemotherapy. Interestingly, aspiration from the Ommaya reservoir revealed regional eosinophilia and an extensive lymphocytic infiltrate [88].…”