Clinical trial of autologous formalin-fixed tumor vaccine for glioblastoma multiforme patients

Abstract

A pilot study was performed to investigate the safety and feasibility of autologous formalin-fixed tumor vaccines (AFTV) and the clinical responses to these vaccines by glioblastoma multiforme (GBM) patients. Twelve primary GBM patients were recruited. Eight had recurrent disease while four had been treated for primary disease but retained a visible tumor mass. AFTV were prepared from formalin-fixed and/or paraffin-embedded tumor tissue obtained upon surgery and premixed with original adjuvant materials. The patients were given three five-site intradermal inoculations at weekly intervals. A delayed-type hypersensitivity test was performed before and after each vaccination. In addition, the tumor tissues were subjected to immunohistochemical analysis to determine whether MIB-1, p53, and major histocompatibility complex (MHC) class-I complex expression could predict the response to the treatment. The treatment was well tolerated, with only local erythema, induration, and low-grade fever being reported. Of the 12 patients, one showed a complete response, one showed a partial response, two showed minor responses, one had stable disease, and seven exhibited progressive disease. The median survival period was 10.7 months from the initiation of the AFTV treatment but three of the five responders survived for 20 months or more after AFTV inoculation. Low p53 and high MHC class-I expression by the tumor may help predict the efficacy of this therapy. Thus, the AFTV is safe and feasible, and could significantly improve the outcome of GBM. Further clinical investigations to confirm this are highly desirable.

Figure 1

Schedule of autologous formalin‐fixed tumor vaccine (AFTV) treatment of glioblastoma multiforme (GBM) patients. Each treatment course consisted of three five‐site intradermal injections of AFTV into the upper arm every week. Delayed‐type hypersensitivity (DTH) tests were performed 48 h before the first vaccination (DTH‐1) and two weeks after the final vaccination (DTH‐2).

Figure 2

Survival curve of autologous formalin‐fixed tumor vaccine (AFTV)‐treated glioblastoma multiforme (GBM) cases. The survival curve of the 12 cases was calculated using the Kaplan–Meier method. Survival times were calculated from the day AFTV therapy was initiated. (a) Three patients survived 20 months or more. The median survival time is 10.7 months. (b) Survival curve of responders (#1, 4, 6, 11, and 12) and non‐responders (#2, 3, 5, 7–10). The median survival time is 20.3 and 5.0 months.

Figure 3

Case #4. This 59‐year‐old woman showed regrowth of a right temporal glioblastoma. After the second surgery, she was inoculated with autologous formalin‐fixed tumor vaccine (AFTV). (a) Serial T1‐weighted MRI with Gadolinium enhancement demonstrate a gradual decrease of the enhanced area with a resolution of mass effect. (b) The maximum reduction was 63%, as shown by plotting the volumetry results against time.

Figure 4

Case #6. This 59‐year‐old man with a right frontal glioblastoma was given the standard initial treatment and then inoculated with autologous formalin‐fixed tumor vaccine (AFTV). (a) Serial T1‐weighted MRI with Gadolinium enhancement demonstrate the irregular enhanced area gradually decreased, eventually disappearing altogether at 20 months after AFTV. (b) Plot of the volumetry results against time. This patient was evaluated to be in complete remission.

Figure 5

HE and immunohistochemical staining of the tumor tissue taken from patient #6. (a) HE staining (×200) shows the typical appearance of glioblastoma multiforme with (b) a high MIB‐1 index of 31%. (c) In the same area, p53 positivity is 6% and (d) there is strong immunoreactivity to an anti‐major histocompatibility complex class‐1 antibody.