Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

Abstract

We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-b2 (TGF-b2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-b in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 Â 10 6 -2 Â 10 7 autologous tumor cells per injection. TGF-b2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-b antisense-modified tumor cells.

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

“…TGF-b2-targeted therapies are currently evaluated in randomised clinical trials (Fakhrai et al, 2006;Schlingensiepen et al, 2006) in consistent with the reports on the relevance of TGF-b2 for the progression of high-grade gliomas. TGF-b2-derived immunosuppression of glioma patients is well described (Jachimczak et al, 1993;Grauer et al, 2006) and plays a pivotal role in glioma progression.…”

Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy

“…These results are surprising given that TGF-h was only inhibited in the vaccine tumor cells and not in the tumor bed and surrounding stroma where the cytokine could be readily produced and exert its immunosuppressive effects to promote tumor progression in the rats. Nevertheless, these preclinical studies led to early clinical trials showing that s.c. injections of these vaccines were well tolerated in phase I and II trials enrolling glioma patients and stage II, III, and IV lung cancer patients (77,78). Elevated serum levels of either IFN-g or immunoglobulins against vaccine cells were noted in some patients on these trials (77,78).…”

“…Nevertheless, these preclinical studies led to early clinical trials showing that s.c. injections of these vaccines were well tolerated in phase I and II trials enrolling glioma patients and stage II, III, and IV lung cancer patients (77,78). Elevated serum levels of either IFN-g or immunoglobulins against vaccine cells were noted in some patients on these trials (77,78). However, it was unclear whether any immune response was elicited against relevant tumor antigens.…”

“…Expression of this vector leads to reduced TGF-h2 expression by the vaccine cells (77), which could be an advantage considering that the endogenous TGF-h generated by the whole-cell vaccine might inhibit its efficacy. Gliosarcoma (9L) cells were stereotactically implanted in the forebrains of Fisher 344 rats and the animals were immunized with irradiated 9L cells stably transfected with a TGF-h2 antisense vector (pCEP-4 TGF-h) 5 days later (79).…”

Tumor antigen precursor protein profiles of adult and pediatric brain tumors identify potential targets for immunotherapy

“…The cytokines have included granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and IL-4 [3][4][5][6]. Genetic engineering of autologous glioma cells to produce immunomodulatory factors, such as antisense TGF-β, has been attempted but timeliness issues have arisen for preparing the individualized treatments for patients with gliomas [7].…”