Autologous Fixed Tumor Vaccine: A Formulation with Cytokine‐microparticles for Protective Immunity against Recurrence of Human Hepatocellular Carcinoma

Abstract

We developed a tumor vaccine consisting of fixed hepatocellular carcinoma (HCC) cells/tissue fragments, biodegradable microparticles encapsulating granulocyte-macrophage-colony stimulating factor and interleukin-2, and an adjuvant. The vaccine protected 33% of syngeneic mice from HCC cell challenge. The vaccine containing human autologous HCC fragments showed essentially no adverse effect in a phase I/IIa clinical trial and 8/12 patients developed a delayed-type hypersensitivity (DTH) response against the fragments. Although 2 of 4 DTH-response-negative patients had recurrence after curative resection, the DTH-response-positive patients had no recurrence. The time before the first recurrence in the vaccinated patients was significantly longer than that in 24 historical control patients operated in the same department (P < < < <0.05). This formulation is a promising candidate to prevent recurrence of human HCC.

Phase II Randomized Trial of Autologous Formalin-Fixed Tumor Vaccine for Postsurgical Recurrence of Hepatocellular Carcinoma

“…2A shown in Ref. 18), S 0(12month) is the rate of recurrence-free survival of the control group at 12 months (this value was 0.375 from Fig. 2A shown in Ref.…”

“…The preparation of AFTV has been described previously (18). Briefly, formalin-fixed HCC tissue (2-3 g wet weight) was fragmented by homogenization and filtered through 70-m nylon meshes, sterilized with 70% alcohol, washed with 0.9% saline, and incubated in RPMI 1640 at 37°C for 2 days to inactivate residual formalin.…”

“…2A shown in Ref. 18), w represents the rate of drop-outs, and Z ␣/2 ϩZ ␤ ϭ 2.801 (from the table of normal distribution; we have set the significance level at 5% and the power of the test at 80%).…”

“…Active specific immunotherapy using the patient's own tumor to elicit a long-term cell-mediated immune response has been used successfully in treatment of melanoma, renal carcinoma, and colon cancer (15)(16)(17). We developed a HCC vaccine consisting of autologous formalin-fixed tumor tissue fragments, biodegradable microparticles containing human granulocyte macrophage colony-stimulating factor and human interleukin 2, and tuberculin (18). In a nonrandomized Phase I/II clinical trial, this vaccine caused few adverse effects and significantly improved the recurrence-free survival of patients who had undergone hepatectomy, compared with historical controls.…”

Pathological Changes After Autologous Formalin-Fixed Tumor Vaccine Therapy Combined With Temozolomide for Glioblastoma -Three Case Reports-

“…7,15) The lesions used to prepare the vaccines were histologically viable GBM tissues with minimal necrotic lesions and no (or minimal) edematic gliosis lesions. All patients received adjuvant TMZ without additional treatment until tumor recurrence.…”