OBJECTIVE

Belagenpumatucel-L is a nonviral gene-based allogeneic tumor cell vaccine that demonstrates enhancement of tumor antigen recognition as a result of transforming growth factor beta-2 inhibition.

METHODS

We performed a randomized, dose-variable, phase II trial involving stages II, IIIA, IIIB, and IV non-small-cell lung cancer patients. Each patient received one of three doses (1.25, 2.5, or 5.0 x 10(7) cells/injection) of belagenpumatucel-L on a monthly or every other month schedule to a maximum of 16 injections. Immune function, safety, and anticancer activity were monitored.

RESULTS

Seventy-five patients (two stage II, 12 stage IIIA, 15 stage IIIB, and 46 stage IV patients) received a total of 550 vaccinations. No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received>> or = 2.5 x 10(7) cells/injection (P = .0069). Focusing on the 61 late-stage (IIIB and IV) assessable patients, a 15% partial response rate was achieved. The estimated probabilities of surviving 1 and 2 years were 68% and 52%, respectively for the higher dose groups combined and 39% and 20%, respectively, for the low-dose group. Immune function was explored in the 61 advanced-stage (IIIB and IV) patients. Increased cytokine production (at week 12 compared with patients with progressive disease) was observed among clinical responders (interferon gamma, P = .006; interleukin [IL] -6, P = .004; IL-4, P = .007), who also displayed an elevated antibody-mediated response to vaccine HLAs (P = .014). Furthermore, positive enzyme-linked immunospot reactions to belagenpumatucel-L showed a correlation trend (P = .086) with clinical responsiveness in patients achieving stable disease or better.

CONCLUSIONS

Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.

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-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta 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 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 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-beta antisense-modified tumor cells.