Antibody Response

To date, 66 patients have been tested for antibodies to PV701 using assays for anti-PV701 IgG antibody and/or neutralizing antibody. Almost all patients were negative for

Fig. 2. Microscopic sections of tumor after eight PV701 cycles in a 46-yr-old man with advanced peritoneal mesothelioma (4 baseline tumor of 8 to 10 cm each) who went on to receive a total of 41 cycles of PV701 and who remained progression-free for 40 mo. (A) Tumor parenchyma demonstrating significant inflammation (H&E staining). (B) Electron micrograph displaying particles consistent with PV701 budding from the tumor cell membrane.

Fig. 2. Microscopic sections of tumor after eight PV701 cycles in a 46-yr-old man with advanced peritoneal mesothelioma (4 baseline tumor of 8 to 10 cm each) who went on to receive a total of 41 cycles of PV701 and who remained progression-free for 40 mo. (A) Tumor parenchyma demonstrating significant inflammation (H&E staining). (B) Electron micrograph displaying particles consistent with PV701 budding from the tumor cell membrane.

any detectable antibodies toward Newcastle disease virus at baseline (1), consistent with previous reports that the general human population is seronegative to this virus (32,33). In most of the patients tested post-dosing, neutralizing antibody titers was first detectable at 1 to 2 wk after their first dose. At 5 to 10 wk post-dosing, the median neutralizing antibody titer was 1:640, which is significantly less than the reported titers for patients treated with adenovirus vectors (34-36). For those patients receiving several courses of PV701, a plateau in neutralizing antibody titer was seen at approx 1:2560 in all 7 cases analyzed thus far, including 1 patient who was followed for the first 18 mo of therapy (1).

Understanding the effects that neutralizing antibodies have on PV701 therapy will require further studies. However, in spite of the presence of neutralizing antibodies, 19 patients receiving more than 1 cycle of PV701 had a second peak in viral shedding in the urine. Among the few patients enrolled with cutaneous metastases, visible signs of inflammation or tumor necrosis were seen in three patients after PV701 dosing during repeat cycles. Importantly, from a clinical perspective, the occurrence of tumor regressions was not restricted to the first two cycles, and included five patients noted to have regressions which developed in later cycles, long after the establishment of neutralizing antibody titers. Additional investigations that will shed further light on these issues will include studies on the immune response to PV701 and studies on viremia, viral clearance and virus levels in tumor biopsies during the initial cycle and during repeat cycles.

Tumor

Fig. 3. Complete response in a 51-yr-old man with tonsillar carcinoma. (A) Baseline MRI scan showing a 1.5-cm tumor in the posterior pharynx. (B) MRI scan at 3 mo demonstrates complete regression of the tumor mass.

Tumor

Fig. 3. Complete response in a 51-yr-old man with tonsillar carcinoma. (A) Baseline MRI scan showing a 1.5-cm tumor in the posterior pharynx. (B) MRI scan at 3 mo demonstrates complete regression of the tumor mass.

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