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Single cell and multicellular organisms encounter physical stress from their environment as well as behavioral stress experienced in more complex organisms. As these stresses can present an existential threat, organisms respond with a coordinated response at the tissue and cellular level, the heat shock response (HSR) and this was the major theme of the symposium. Much of the meeting was concentrated on the heat shock proteins (HSPs), the effector molecules of the response. The balance between the potency of the HSR and the experience of stress naturally plays a key role in the etiology of many disease. Roles in cancer, the immune response, cell metabolism and aging were discussed at length at the meeting. Finally, a major goal of this field is to enhance the HSR in pathological conditions where it becomes inadequate or over stimulated and important findings regarding pharmacological approaches to modulating the HSR were discussed.

Heat shock proteins (hsp) are intracellular chaperones that possess extracellular immunostimulatory properties when complexed with antigens. A recombinant Hsp110-gp100 chaperone complex vaccine showed an antitumor response and prolonged survival in murine melanoma. A phase Ib dose-escalation study of a recombinant human Hsp110-gp100 vaccine in advanced-stage melanoma patients was performed to evaluate toxicity, immunostimulatory potential and clinical response. Patients with pretreated, unresectable stage IIIB/C/IV melanoma received the chaperone complex vaccine in a dose-escalation protocol; three vaccinations over a 43-day-period. Tumor response, clinical toxicity and immune response were measured. Ten patients (eight female, median age 70 years) were enrolled and two patients had grade 1 adverse events; minor skin rash, hyperhidrosis and fever (no grade 2 or higher adverse events). Median progression-free survival was longer for lower vaccine doses as compared to the maximum dose of 180 mcg (4.5 vs. 2.9 months; P = 0.018). The lowest dose patients (30 and 60 mcg) had clinical tumor responses (one partial response, one stable disease). CD8+ T cell interferon-γ responses to gp100 were greater in the clinically responding patients. A pattern of B cell responses to vaccination was not observed. Regulatory T cell populations and co-stimulatory molecules including cytotoxic T-lymphocyte-associated protein 4 and PD-1 appeared to differ in responders versus nonresponders. A fully recombinant human Hsp110-gp100 chaperone complex vaccine had minimal toxicity, measurable tumor responses at lower doses and produced peripheral CD8+ T cell activation in patients with advanced, pretreated melanoma. Combination with currently available immunotherapies may augment clinical responses.

We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker.A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes.A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82).Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Rituximab is a chimeric antibody (Ab) directed against the cluster designated (CD) 20 antigen found on normal and malignant B cells. Rituximab activity has been associated with complement-mediated cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. Recent studies performed in severe combined immunodeficiency (SCID) mouse models suggest that in vivo rituximab-associated ADCC is mediated via the FcgammaRIII receptor on effector cells. Despite low level expression of FcgammaRIII, neutrophils are also known to induce ADCC primarily via FcgammaRI receptor (CD64). The purpose of this work was to study the effect(s) of neutrophils on the in vivo antitumor activity of rituximab.To better characterize the biological activity of rituximab, we used a human non-Hodgkin's lymphoma animal model by injecting Raji cells i.v. into natural killer (NK) cell-depleted SCID mice. Disseminated disease involving liver, lung, and central nervous system developed, with subsequent death occurring approximately 3 weeks after tumor inoculation. Specifically, 6-8-week-old NK cell-depleted SCID mice were inoculated by tail vein injection with 1 x 10(6) Raji cells on day 0. The animals then were divided into three cohorts: (a) group A received placebo (PBS); (b) group B received rituximab administered via tail vein injection at 10 mg/kg on days 3, 5, 7, and 11; and (c) group C consisted of neutrophil-depleted SCID mice treated with rituximab at 10 mg/kg on the same schedule. Neutrophils were depleted by i.p. administration of 80 microg of rat antimouse Ly-6G (Gr-1) Ab (BD PharMingen, Inc.) on days -1, 4, 9, and 14. The end point of the study was survival. Differences in outcome between treatment groups were analyzed by Kaplan-Meier methodology.Neutrophil- and NK cell-depleted SCID mice (group C) did not respond to rituximab, and the mean survival time was not significantly different from that of control mice. NK cell-depleted SCID mice with intact neutrophil function (group B) responded to rituximab, and 66% remained alive and appeared healthy after a mean follow-up period of 246 days. Overall, NK cell-depleted SCID mice with intact neutrophil function treated with rituximab had statistically longer mean survival as compared with mice in neutrophil-depleted and control groups (161 days versus 28 days versus 22 days, P=0.003).In the absence of neutrophils, rituximab was less effective in controlling lymphoma cell growth or prolonging survival in our B-cell lymphoma SCID mouse model. Neutrophil-induced ADCC appears to contribute to the in vivo antitumor activity of rituximab. Strategies that improve the function of neutrophils, such as granulocyte-macrophage colony-stimulating factor or G-CSF priming, may increase the antitumor effects of rituximab. Additional in vivo animal studies are warranted.