Neurobehavioral Effects of Interferon-α in Cancer Patients: Phenomenology and Paroxetine Responsiveness of Symptom Dimensions

PGE 2 is a well-known immunomodulator produced in the immune response by APCs, such as dendritic cells (DCs), the most potent APC of the immune system. We investigated the PGE 2 biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE 2 and other proinflammatory mediators, such as leukotriene B 4 and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE 2 compared with the LPS-induced COX-2-produced PGE 2 . Treatment of BM-DC with exogenous PGE 2 induced the production of large amounts of IL-10 and less IL-12p70. In addition, selective inhibition of COX-2, but not COX-1, was followed by significant decrements in PGE 2 and IL-10, a concomitant restoration of IL-12 production, and an enhancement of DC stimulatory potential. In contrast, we found no demonstrable role for leukotriene B 4 or NO. In view of the potential of PGE 2 to stimulate IL-10, we examined the possibility that the suppressive effect of PGE 2 is mediated via IL-10. We found that exogenous IL-10 inhibits IL-12p70 production in the presence of NS-398, a COX-2 selective inhibitor, while the inhibitory effects of PGE 2 were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE 2 up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.

Cyclooxygenase-2-issued prostaglandin e(2) enhances the production of endogenous IL-10, which down-regulates dendritic cell functions.

Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years?

A melanoma vaccine composed of HLA-A2-restricted peptide YLEPGPVTA (gp100(280)), with or without a modified T-helper epitope from tetanus toxoid AQYIKANSKFIGITEL, has been evaluated in a Phase I trial to assess safety and immunological response. The vaccines were administered s.c. in either of two adjuvants, Montanide ISA-51 or QS-21, to 22 patients with high-risk resected melanoma (stage IIB-IV). Local and systemic toxicities were mild and transient. We detected CTL responses to the gp100(280) peptide in peripheral blood in 14% of patients. Helper T-cell responses to the tetanus helper peptide were detected in 79% of patients and had a Th1 cytokine profile. One patient with a CTL response to gp100 had a recurrence in a lymph node 2 years later; her nodes contained CD8+ cells reactive to gp100(280) (0.24%), which proliferated in response to peptide. The overall survival of patients is 75% (95% confidence interval, 57-94%) at 4.7 years follow-up, which compares favorably with expected survival. Four of 14 patients who completed at least six vaccines subsequently developed metastases, all of which were solitary and surgically resectable. They remain alive and clinically free of disease at last follow-up. Data from this trial demonstrate immunogenicity of the gp100(280) peptide and suggest that immune responses may persist long-term in some patients. The frequency and magnitude of the CTL response may be improved with more aggressive vaccination regimens. Although this Phase I study was not intended to evaluate clinical benefit, the excellent survival of patients on this protocol suggests the possibility of a benefit that should be assessed in future studies.

https://clincancerres.aacrjournals.org/content/clincanres/7/10/3012.full.pdf

Phase I trial of a melanoma vaccine with gp100(280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes.

Management of Metastatic Melanoma

The aim of the protocol was to evaluate the side-effects induced by repeated tumour-infiltrating lymphocyte (TIL) infusions in patients with metastatic melanoma (MM). Patients were to receive four TIL infusions at given intervals: every 3 weeks (two patients), every 2 weeks (3 patients) and weekly (4 patients). All patients were evaluated and received a total of 34 TIL infusions. The total number of TILs administered varied from 0.65 to 2.34 x 10(11) cells. TIL phenotypes were predominantly CD8+ (two patients), CD4+ (4 patients), CD4+ then CD8+ (two patients) or CD56+ (two patient). Autocytotoxicity was only observed for one culture. Six patients presented at least one WHO grade 3 side-effect: hypotension (5 patients), dyspnoea (two patients), fever (one patient), fatigue (one patient), chills (two patients), diarrhoea (one patient), agitation (one patient), locoregional pain (two patients). Hypotension was constantly seen in patients who were given TILs every week. Two cases of minor pericarditis were recorded. No objective response to treatment was observed; 1 stable disease occurred in one patient and progression in eight. However, five patients presented a partial response on a tumour site for 1-4 months. Three patients presented signs of inflammation or softening at one tumour site. Plasma tumour necrosis factor alpha (TNF-alpha) levels were increased 1.2- to 22-fold after TIL infusion. TILs could be produced in sufficient quantity to perform this study, so repetitive infusions of TIL became possible on a weekly basis. However, no objective response was observed even when TIL infusions were performed weekly. An increase in circulating TNF-alpha was noted after TIL infusion.

A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma.

To assess the feasibility and toxicity profile of high-dose interferon alpha-2b (IFN-alpha-2b) in the adjuvant treatment of patients with cutaneous malignant melanoma outside the reference ECOG 1684 clinical trial, we conducted a prospective follow-up in an identical population of patients (cutaneous melanoma, T4 and/or N1) treated by intravenous IFN-alpha-2b:20 MIU m(-2), 5 days a week for 4 weeks; and subcutaneous:10 MIU m(-2), 3 times a week for 11 months. Thirty-six consecutive patients were considered in four different institutions. The frequency and severity of side-effects related to IFN-alpha, as well as the percentage of the planned dose given to patients, were identical to those reported in the initial report by ECOG. Fifty per cent and 47% of patients had a grade 3/4 WHO toxicity in the induction and consolidation phase respectively. A dose modification was necessary for 47.2% and 55.8% of the patients in the induction and consolidation phase respectively. The schedule and dose of high-dose IFN-alpha-2b in the adjuvant treatment of cutaneous malignant melanoma, as reported by ECOG 1684, is feasible. The significant toxicity reported in ECOG 1684 was also seen in our patients. Nevertheless, this protocol will not be a 'standard' treatment until the publication of the ECOG 1690 trial.

/pdf/toxicity-and-feasibility-of-adjuvant-high-dose-interferon-4f8j67mpco.pdf

Toxicity and feasibility of adjuvant high-dose interferon alpha-2b in patients with melanoma in clinical oncologic practice

The potential antitumoral effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) led us to evaluate GM-CSF alone or with dacarbazine (DTIC) in metastatic melanoma in first line randomized phase II. Treatment was arm A: GM-CSF: 5 microg kg(-1), bid, 14 consecutive days every 21 days and arm B: GM-CSF: 5 microg kg(-1), bid, day 2 to day 19 every 21 days and DTIC: 800 mg m(-2), day 1 of each cycle. 32 patients (pts) were included, 15 pts in arm A and 17 in arm B. All pts had visceral metastatic sites. 9 had only one metastatic site. The median number of cycles given was 2 in arm A and 3 in arm B. 100% and 89.4% of the planned dose of GM-CSF was given in arm A and arm B respectively. No objective response was obtained. 19 pts experienced at least WHO grade 3 toxicity. All pts had fever, 29 had a decrease in performance status and 23 had pain. Grade 3 toxicity were fever (38.7%), decrease in performance status (32.3%), pain (19.4%) and dyspnoea (12.5%). In this study, GM-CSF alone or in association with DTIC did not induce any antitumoral activity with subsequent toxicity.

/pdf/granulocyte-macrophage-colony-stimulating-factor-alone-or-2pn749a156.pdf

Granulocyte-macrophage colony-stimulating factor alone or with dacarbazine in metastatic melanoma: a randomized phase II trial.

Presentation of cell-associated antigen to T cells is a critical event in the initiation of an anti-tumor immune response but it appears to often be deficient or limiting. Here we report an experimental system for stimulation of human T lymphocytes using autologous antigen presenting cells (APCs) and autologous tumor cells. Two types of APCs were prepared from human bone marrow: MC and DC. MC were produced by using GM-CSF and SCF. DC were obtained with the same cytokines plus IL-4. DC and MC were generated in parallel from the same patients and their phenotypes and capacities to prime T lymphocytes were analyzed and compared. MC were CD14+, CD1a-, CD33+ and HLA-DR+. Two populations of DC were defined: immature DC were uniformly CD1a-; mature DC expressed CD1a, CD80, CD86, HLA-DR, CD54 and CD58 but lacked surface CD14. Stimulation of autologous T lymphocytes was studied by measuring their proliferation and cytotoxic function. In more than 80% of our experiments the proliferation of autologous T lymphocytes cocultured with APC pulsed or not with tumor cell lysates was higher than that of T cells cultured alone. DC were more effective than MC in stimulating proliferation of lymphocytes. The capacity of a patient's autologous bone marrow-derived APC to stimulate T cells when exposed to autologous tumor cell lysates suggest that such antigen-exposed APC may be useful in specific anti-tumor immunotherapy protocols.

In vitro immunization of patient T cells with autologous bone marrow antigen presenting cells pulsed with tumor lysates.

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A phase I trial of repeated tumour-infiltrating lymphocyte (TIL) infusion in metastatic melanoma.

Toxicity and feasibility of adjuvant high-dose interferon alpha-2b in patients with melanoma in clinical oncologic practice

Granulocyte-macrophage colony-stimulating factor alone or with dacarbazine in metastatic melanoma: a randomized phase II trial.

In vitro immunization of patient T cells with autologous bone marrow antigen presenting cells pulsed with tumor lysates.