Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

Abstract

Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mg of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNAhsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

“…11, Group B) showing borderline proliferation (SI ¼ 2.06) 1 week after the third dose of vaccine. This patient showed stable disease, with a 2% reduction in tumor volume between the two evaluations, and eventually died of disease progression 228 days after the beginning of treatment ( Table 2; Michaluart et al 8 ).…”

“…These data suggest that the modulation in IL-10 production was not specific to Hsp65, but could reflect a more general modulation in the global activation state of the patients, as described in the clinical trial paper. 8 As discussed below, production of IL-10 appears to be unrelated to clinical progress.…”

“…Each patient received three doses of the indicated amount of DNA-hsp65, administered by ultrasonography-guided intratumoral injection at 3-week intervals, as previously described. 8 …”

“…The third patient, no. 21, had an intense clinically diagnosed local inflammatory response to the vaccine, including pain, edema and lymph-node engorgement, 8 and showed the greatest increase in both antibody levels and IL-10 production to Hsp65. This patient also showed a concomitant decrease in lymphoproliferation-which may indicate the negative influence of the intense IL-10 production-and negative PPD following vaccination.…”

“…8 In this study, the toxicity and side effects of different doses of DNA-hsp65 were evaluated in 21 patients; however, the immune response elicited by vaccination was not extensively characterized. Although data from the animal models suggest that specific immune response to Hsp65 does not seem to be critical for the vaccine's antitumoral effects in cancer, 7 the proposed use of DNA-hsp65 for the prevention and treatment of tuberculosis and the fact that this is the first time this vaccine is used in humans justify further analysis of its immunogenic potential.…”