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Introduction: In contemporary oncology drug development, implementation of novel early-phase designs with the ability to address multiple research objectives is needed to better refine regimens. This paper describes an adaptive design strategy for identifying a range of optimal regimens based on two endpoints within multiple cohorts. The proposed design was developed to address objectives in an early-phase trial of cancer vaccines in combination with agonistic antibodies to CD40 and CD27. Materials and methods: We describe a model-based design strategy that was developed for a trial evaluating the safety and immunogenicity of vaccination with (1) peptides plus CD40 antibody and TLR3 ligand, (2) systemic administration of an agonistic CD27 antibody, and (3) to assess immune response from (1) and (2) compared to optimal controls in participants with stage IIB-IV melanoma. Results and conclusions: The proposed design is a practical adaptive method for use with combined immunotherapy regimens with multiple objectives within multiple cohorts of interest. Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining optimal strategies to take multiple regimens forward into later phases, incorporating additional endpoints in the dose selection process and testing drug combination therapies to improve efficacy and reduce toxicity. Our goal is to facilitate the acceptance and application of more novel designs in contemporary early development trials. [ABSTRACT FROM AUTHOR]

Introduction: Infiltration of non-small-cell lung cancer (NSCLC) by CD8 T lymphocytes predicts improved patient survival; however, heterogeneity of intratumoral localization complicates this assessment. Strategies for tumor sampling may not accurately represent the whole tumor. We hypothesized that sampling strategies may alter the identification of tumors with high CD8 density and affect the prognostic significance. Patients and methods: Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson's r). Associations between CD8 densities and overall survival were assessed (log-rank test). Results: Counts from all eight sampling strategies significantly correlated with whole tumor counts ( p ≤ 0.001). However, the magnitude of CD8 cell counts and categorization into high vs low infiltrate groups were affected by the sampling strategy. The most concordant values were derived from random sampling of 20 % of the tumor, a simulated core biopsy, or from sampling the tumor center. TIL infiltration was associated with survival when sampling the center ( p = 0.038), but not the invasive margin ( p > 0.2) or other strategies. Conclusion: Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8 T cells in the tumor center may have prognostic value. [ABSTRACT FROM AUTHOR]

Introduction: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. Patients and methods: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. Results and conclusions: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Introduction: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases. Patients and methods: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. Results: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. Conclusion: The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases. [ABSTRACT FROM AUTHOR]

Background: The impacts of patient age and gender on immune response (IR) and clinical outcome after cancer vaccines are not known. We hypothesized younger and female patients would have higher IR rates and better survival. Methods: Patients with resected stage IIB-IV melanoma in three clinical trials (Mel43, Mel44, Mel48) were vaccinated with 12 melanoma-associated peptides restricted by class I MHC. The cumulative incidence rate of CD8 T cell responses (direct interferon-gamma ELIspot assay) by week 7 was compared by age and gender. Overall survival (OS) and disease-free survival (DFS) landmark analyses were compared by Kaplan-Meier estimates and in multivariate analyses. Results: T cell responses were evaluated in 327 patients and detected in 50 % of males and 48 % of females, with no difference in IR by gender or menopausal status. Males had trends toward longer DFS ( p = 0.12) and OS ( p = 0.09). Cumulative incidence of IR was higher in patients <64 years of age versus older patients ( p = 0.03). OS and DFS were similar by age group ( p > 0.50). In multivariate modeling, younger age was associated with better IR (OR 0.40, p value 0.003), without an impact of age or gender on clinical outcomes. Conclusion: These data support the hypothesis that older patients are less likely to develop T cell responses to a cancer vaccine. Nonetheless, significant proportions of older patients mount immune responses with comparable survival outcomes. Thus, these data support including older patients in cancer vaccine trials, but suggest value in stratifying patients by age 64 years. [ABSTRACT FROM AUTHOR]