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The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

Gradient descent, or negative gradient flow, is a standard technique in optimization to find the minima of functions. Many implementations of gradient descent rely on discretized versions, i.e. moving in the gradient direction for a set step size, recomputing the gradient and continuing. In this paper, we present an approach to manifold learning where gradient descent takes place in the infinite-dimensional space ℰ = Emb(M, ℝN) of smooth embeddings ϕ of a manifold M into ℝN. Implementing a discretized version of gradient descent for P : ℰ→ ℝ, a penalty function that scores an embedding ϕ ∈ℰ, requires estimating how far we can move in a fixed direction — the direction of one gradient step — before leaving the space of smooth embeddings. Our main result is to give an explicit lower bound for this step length in terms of the Riemannian geometry of ϕ(M). In particular, we consider the case when the gradient of P is pointwise normal to the embedded manifold ϕ(M). We prove this case arises when P is invariant under diffeomorphisms of M, a natural condition in manifold learning. [ABSTRACT FROM AUTHOR]

We examined relationships between measures of adaptive behavior, cognitive ability, and autism symptom severity in 1458 preschool-aged children with autism from the Study to Explore Early Development. While publications commonly describe autistic children as "low-" or "high-functioning" based on cognitive ability, relying solely on cognitive scores may obscure meaningful variation in functioning. We found significant heterogeneity in adaptive behavior scores of children with cognitive scores both above and below the threshold of two or more standard deviations below the population mean specified in the diagnostic criteria for intellectual disability (ID). Although cognitive and adaptive behavior scores were strongly associated in our sample, considerable variation in overall adaptive behavior and more than half in socialization and motor skills was unaccounted for by cognitive ability, autism symptom severity, and other covariates. Among children who could be designated "low-functioning" based on cognitive scores, 39.7% had composite adaptive behavior scores indicating no significant delays, while among those who might be designated "high-functioning," 9.0% had significant delays in overall adaptive behavior and 22.2% in socialization. These results suggest adaptive behavior scores capture variations in the autism phenotype not accounted for by other measures we considered. Autistic people are often described as "low-" or "high-functioning" based on their scores on cognitive tests. These terms are common in publications and in everyday communication. However, recent research and feedback from the autistic community suggests that relying on cognitive ability alone to describe functioning may miss meaningful differences in the abilities of autistic children and adults and in the kinds of support they may need. Additional methods are needed to describe "functioning" in autistic children. We examined whether scores from a test measuring adaptive behaviors would provide information on the functional abilities of children with autism that is different from cognitive ability and autism symptom severity. Adaptive behaviors include age-appropriate skills that allow people to function in their everyday lives and social interactions. We found that a large amount of the variation in adaptive behavior scores was not explained by cognitive development, autism symptom severity, and behavioral and emotional problems. In addition, there was a wide range of adaptive ability levels in children with autism in our study, including in those with low, average, or high cognitive scores. Our results suggest that adaptive behavior scores could provide useful information about the strengths and support needs of autistic children above and beyond measures of cognitive ability and autism symptom severity. Adaptive behavior scores provide important information on the needs of autistic people. [ABSTRACT FROM AUTHOR]

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote 'off-the-shelf' precision immunotherapies, alleviating limitations of personalized treatments., Introduction Immunotherapy sparked new hope for oncology in recent years, due to its remarkable ability to induce long-term tumor regression of metastatic cancer. This feature is shared across immunotherapeutic modalities, [...]