Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.

Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8(+) T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8(+) T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8(+) T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.

Evaluating the criterion validity of hierarchical psychopathology dimensions across models: Familial aggregation and associations with research domain criteria (sub)constructs.

The Hierarchical Taxonomy of Psychopathology (HiTOP) posits that psychopathology is a hierarchy of correlated dimensions. Numerous studies have examined the validity of these dimensions using bifactor models, in which each disorder loads onto both a general and specific factor (e.g., internalizing, externalizing). Although bifactor models tend to fit better than alternative models, concerns have been raised about bifactor model selection, factor reliability, and interpretability. Therefore, we compared the reliability and validity of several higher-order HiTOP dimensions between bifactor and correlated factor models using familial aggregation and associations with Research Domain Criteria (RDoC; sub)constructs as validators. Lifetime psychopathology was assessed in a community sample (N = 504) using dimensional disorder severity scales calculated from semistructured interview data. A series of unidimensional, correlated factor, and bifactor models were fit to model several HiTOP dimensions. A bifactor model with two specific factors (internalizing and disinhibited externalizing) and a correlated two-factor model provided the best fit to the data. HiTOP dimensions had adequate reliability in the correlated factor model, but suboptimal reliability in the bifactor model. The disinhibited externalizing dimension was highly correlated across the two models and was familial, yet largely unrelated to RDoC (sub)constructs in both models. The internalizing dimension in the correlated factor model and the general factor in the bifactor model were highly correlated and had similar validity patterns, suggesting the general factor was largely redundant with the internalizing dimension in the correlated factor model. These findings support concerns about the interpretability of psychopathology dimensions in bifactor models. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Malignant melanoma-The cradle of anti-neoplastic immunotherapy.

One of the defining characteristics of the malignant phenotype is the ability to evade the host immune system. Immunotherapy as a treatment modality represents a new dawn in the way we think about the treatment of a variety of malignancies. The story of immunotherapy traces its roots to its relationship with malignant melanoma. In this article, we review the intertwined history of immunotherapy and melanoma, including the early significant history, a discussion on immune mechanisms, resistance, local and systemic immunotherapeutic modalities, and speculate on possible novel future treatment options.