Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains lethal. Chimeric antigen receptor (CAR) T cell therapies have demonstrated durable remissions in hematological malignancies. We report results from a phase 1, first-in-human study of prostate stem cell antigen (PSCA)-directed CAR T cells in men with mCRPC. The starting dose level (DL) was 100 million (M) CAR T cells without lymphodepletion (LD), followed by incorporation of LD. The primary end points were safety and dose-limiting toxicities (DLTs). No DLTs were observed at DL1, with a DLT of grade 3 cystitis encountered at DL2, resulting in addition of a new cohort using a reduced LD regimen + 100 M CAR T cells (DL3). No DLTs were observed in DL3. Cytokine release syndrome of grade 1 or 2 occurred in 5 of 14 treated patients. Prostate-specific antigen declines (>30%) occurred in 4 of 14 patients, as well as radiographic improvements. Dynamic changes indicating activation of peripheral blood endogenous and CAR T cell subsets, TCR repertoire diversity and changes in the tumor immune microenvironment were observed in a subset of patients. Limited persistence of CAR T cells was observed beyond 28 days post-infusion. These results support future clinical studies to optimize dosing and combination strategies to improve durable therapeutic outcomes. ClinicalTrials.gov identifier NCT03873805.

Chimeric antigen receptor (CAR)-T cell efficacy in solid tumours is limited due in part to the immunosuppressive tumour microenvironment (TME). To improve antitumour responses, we hypothesized that enabling CAR-T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier such as TGFβ^trap, IL-15 or IL-12, combined with an immune checkpoint inhibitor such as αPD-L1, would provide tumour-localized immunomodulation to improve CAR-T cell functionality. Here we engineer CAR-T cells to secrete TGFβ^trap, IL-15 or IL-12 molecules fused to αPD-L1 scFv and assess in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR-T cells engineered with αPD-L1–IL-12 are superior in safety and efficacy compared with CAR-T cells alone and those engineered with αPD-L1 fused with TGFβ^trap or IL-15. Further, αPD-L1–IL-12 engineered CAR-T cells improve T cell trafficking and tumour infiltration, and localize IFNγ production, TME modulation and antitumour responses, with reduced systemic inflammation-associated toxicities. We believe our αPD-L1–IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types.

Background: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern.BRCA1andBRCA2are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20–30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants inATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN,andTP53genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients.Methods: We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1,ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53andUIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions inBRCA1/BRCA2genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms.Results: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants inBRCA1, BRCA2andTP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant inATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants inABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2,andPMS2genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions inBRCA1/BRCA2genes.Conclusions: This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.

Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder.