Dale Ando

Granulocyte Macrophage Colony-Stimulating Factor–Secreting Allogeneic Cellular Immunotherapy for Hormone-Refractory Prostate Cancer

Purpose: This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naïve patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene. Experimental Design: HRPC patients with radiologic metastases (n = 34) or rising prostate-specific antigen (PSA) only (n = 21) received a prime dose of 500 million cells and 12 boost doses of either 100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival. Results: Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose (n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose (n = 24). The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group (n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue. Conclusions: These results suggest that this GM-CSF–secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.

Comparison of Serum Interleukin-10 (IL-10) Levels Between Normal Volunteers and Patients with Advanced Melanoma

Melanoma is an immunoresponsive malignancy. Interleukin-10 (IL-10) is a potent regulator of immunosuppression. The purpose of this research was to define the relationship of serum IL-10 to survival in patients with metastatic melanoma. Forty-one melanoma patients and 50 normal volunteers were analyzed. The median IL-10 level as determined by enzyme-linked immunosorbent assay (ELISA) in melanoma patients was 8.75 pg/ml compared to <3.0 pg/ml in normal volunteers (p = 0.0001). Survival of melanoma patients with an IL-10 level above 10.0 pg/ml was 365 days compared to 557 days in patients with IL-10 levels less than 10.0 pg/ml (p = 0.0259, Wilcoxon). Elevated IL-10 levels were correlated with poor survival.

The oncolytic virotherapy treatment platform for cancer: Unique biological and biosafety points to consider

The field of replication-selective oncolytic viruses (virotherapy) has exploded over the last 10 years. As with many novel therapeutic approaches, initial overexuberance has been tempered by clinical trial results with first-generation agents. Although a number of significant hurdles to this approach have now been identified, novel solutions have been proposed and improvements are being made at a furious rate. This article seeks to initiate a discussion of these hurdles, approaches to overcome them, and unique safety and regulatory issues to consider.

Phase I Trial of Interferon gamma Retroviral Vector Administered Intratumorally with Multiple Courses in Patients with Metastatic Melanoma

The purpose of this study was to determine the safety and antitumor activity of IFN-gamma retroviral vector in patients with advanced melanoma. Seventeen patients (9 single courses, 8 multiple courses) received a total of 363 intratumor injections of IFN-gamma retroviral vector (1 x 10(7) PFU/ml administered at 0.3, 0.5, and 1.0 ml per cohort). No grade III/IV adverse events were attributed to study medication. Replication-competent retrovirus was not detected in any of the 17 patients by polymerase chain reaction studies. Eight patients showed elevated anti-tumor antibody responses in comparison with baseline by ELISA. One of nine patients treated with a single course had an optimal response of stable disease, compared with eight of eight multiple-injected patients. Median survival of single-injected patients was 150 days, and patients who received multiple injections have still not achieved median survival duration, with four of eight still living (p = 0.0462, Wilcoxon; p = 0.0273, log rank). We conclude that intratumor injection of IFN-gamma is safe and well tolerated. Evidence of antitumor activity is suggested in patients with advanced malignancy that received multiple injections.

Induction of melanoma-associated antigen systemic immunity upon intratumoral delivery of interferon-gamma retroviral vector in melanoma patients.

A total of 17 patients with metastatic melanoma were treated with intratumoral interferon-γ (IFN-γ) retroviral vector in a phase I clinical trial. A cycle of treatment consisted of five daily injections every 2 weeks. Patients were divided into two treatment arms that involved a single course (one cycle) of treatment (group I; n = 9) and multiple cycles (six cycles) of treatment (group II; n = 8). Patients received intratumoral injections of IFN-γ (107 plaque-forming units/mL administered at 0.3, 0.5, and 1.0 mL per cohort of patients). All patients receiving multiple injections either maintained stable disease (n = 5) or achieved a partial or complete response (n = 3) of the injected lesion, whereas in patients receiving a single cycle of treatment, only one of nine patients had a response. Patients were assessed for immunoglobulin G antibody (Ab) responses to the melanoma-associated antigens (MAA) tyrosinase, gp100, TRP-2, and MAGE-A1 by affinity enzyme-linked immunosorbent assay. Anti-MAGE-A1 and tyrosinase Ab were significantly elevated from baseline (day 0) to week 16 during treatment (P = .005; P = .002, respectively) in patients who received multiple injections. Patients undergoing treatment who had a clinical response (stable disease or better) also had significantly more elevated Ab responses to a greater number of MAA (P = .0004). The induction of systemic Ab responses to multiple MAA also correlated with systemic clinical responses. These studies suggest that multiple anti-MAA Ab responses are associated with clinical responses to IFN-γ retroviral treatment and may be used as surrogate response markers.

Phase I trial of interferon-γ (IFN-γ) retroviral vector administered intratumorally to patients with metastatic melanoma

Background: Interferon-γ (IFN-γ) gene/retroviral vector cell vaccinations have generated protective responses from unmodified tumor cell challenges as well as a regression of established tumors in animal models. The purpose of this trial was to determine the feasibility and safety of a direct intratumoral injection of IFN-γ retroviral vector in advanced melanoma patients.Methods: This was a phase I study, in which 13 patients received a single daily injection of a retroviral vector with the IFN-γ gene for 5 consecutive days (1.5 × 108 colony-forming units total dose); patients subsequently underwent resection of the injected lesion to confirm DNA transduction in situ.Results: No toxicity related to the injected vector was observed. Replication competent retrovirus was not observed in any prepared samples (n = 65). IFN-γ expression was confirmed in 3 of 10 harvested tumor samples; one was equivocal, and DNA transduction was unable to be confirmed by enzyme-linked immunospot assay in six samples.Conclusions: An injection of IFN-γ gene/retroviral vector is well tolerated. DNA transduction was demonstrated in human subjects, confirming the feasibility of the direct injection approach for the gene therapy of solid tumors. Further trials to determine optimal schedule and potential efficacy are indicated.

Department of Health and Human Services National Institutes of Health Recombinant DNA Advisory Committee. Minutes of meeting March 8-10, 2000.

NATIONAL INSTITUTES OF HEALTH National Eye Institute (NEI) FY 2018 Budget Page No. Organization Chart...........................................................................................................................2 Appropriation Language ..................................................................................................................3 Amounts Available for Obligation...................................................................................................4 Budget Graphs .................................................................................................................................5 Authorizing Legislation ...................................................................................................................6 Appropriations History ....................................................................................................................7 Justification of Budget Request .......................................................................................................8 Detail of Full-Time Equivalent Employment (FTE) .....................................................................15 Detail of Positions ..........................................................................................................................16