Oncology:

PURPOSE: Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).

PURPOSE: To investigate the clinical behavior of breast cancer in young carriers according to the specific gene () and the association of the timing of genetic testing (before at diagnosis) with prognosis.

PURPOSE: Organ preservation has become an attractive alternative to surgery (total mesorectal excision [TME]) among patients with rectal cancer after neoadjuvant therapy who achieve a clinical complete response (cCR). Nearly 30% of these patients will develop local regrowth (LR). Although salvage resection is frequently feasible, there may be an increased risk for development of subsequent distant metastases (DM). The aim of this study is to compare the risk of DM between patients with LR after Watch and Wait (WW) and patients with near-complete pathologic response (nPCR) managed by TME at the time of reassessment of response.

PURPOSE: Relapsed high-risk neuroblastomas (NBLs) are enriched for targetable mutations in and RAS-MAPK pathways, yet the prognostic effect of these aberrations and relevance of subclonal mutations at diagnosis remain undefined. We describe the spectrum and clinical significance of clonal and subclonal pathogenic alterations in high-risk NBL.

Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions.

No abstract available

Apolipoproteins are the defining functional component of lipoproteins and play critical roles in lipid transport and metabolism. High-density lipoprotein (HDL) and its primary functional constituent, apolipoprotein A-I, are of particular importance because of anti-inflammatory and antioxidant properties. Apolipoprotein mimetic peptides are short-chain amino acids designed to mimic the functions and alpha-helical structure of endogenous apolipoproteins and have demonstrated efficacy in ameliorating animal models of cardiovascular disease (CVD) and cancer. The mechanisms underlying the mimetics are yet to be fully elucidated, but a comprehensive review of the literature suggests that the peptides attack pathways shared in the pathophysiology of both diseases. This review also discusses the many pre-clinical studies on the mimetic peptides, highlighting possible mechanisms at work in each. Proposed mechanisms of protection against CVD and cancer include binding and removal of pro-inflammatory oxidized lipids, reduction in reactive oxygen species, and modulation of immune cell populations. Additionally, nanoparticles (NP) formulations incorporating apolipoprotein mimetic peptides or recombinant apolipoproteins have exhibited anti-atherogenic and anti-cancer activity. To date, clinical trials to assess the effect of reconstituted HDL NPs on CVD outcomes have not shown significant improvement. The large body of successful animal studies on apolipoproteins and apolipoprotein mimetic peptides presents a disconnect between pre-clinical and clinical efficacy, highlighting the need for a more complete understanding of the underlying pathways and mechanisms.

PURPOSE: Anti-vascular endothelial growth factor therapy enhances PD-1 inhibitor activity in preclinical models and has been used to treat perilesional cerebral edema and radiation necrosis.

Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) has poor outcomes. We analyzed 1,611 patients with AML and 4.3% demonstrated rearrangements in KMT2A. Signaling-related genes (NRAS 30%, KRAS 23% and FLT3-TKD 16%) were the most frequently mutated in patients with KMT2Ar AML. Patients treated with intensive chemotherapy (IT) achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) rate of 81%, and when combined with venetoclax, the CR/CRi rate increased to 100%. Patients treated with low intensity treatment (LIT) achieved an CR/CRi rate of 33%, and when combined with venetoclax, the CR/CRi rate was 61%. For patients treated with IT, the 5-year overall survival (OS) and event-free survival (EFS) rates were 66% and 64%, respectively, compared with 7% in those treated with LIT. Thirty-nine patients (57%) underwent allogeneic stem cell transplantation after achieving CR/CRi. For patients treated with LIT, multivariate analysis demonstrated that N/KRAS mutations were predictive for OS (HR 2.93, 95% CI 1.18-7.29, P = 0.021) and EFS (HR 3.51, 95% CI 1.35-9.24, P = 0.01). In summary, outcomes in KMT2Ar AML have improved over years in patients treated with IT, whereas those treated with LIT continue to show poor survival, highlighting the need for novel combinations.

PURPOSE: The standard of care for metastatic castration-resistant prostate cancer (mCRPC) after second-generation androgen receptor pathway inhibitor (ARPI) therapy is still docetaxel. The randomized, double-blind, phase III KEYNOTE-921 trial (Clinicaltrials.gov identifier: NCT03834506) evaluated the efficacy and safety of pembrolizumab or placebo plus docetaxel for previously treated mCRPC.

Drugs targeting metabolism have been effectively used in patients with T-cell acute lymphoblastic leukemia (T-ALL) for decades; still, the full therapeutic potential of targeting metabolism has not been completely exploited yet. Here, we highlight the critical need for metabolic biomarkers to advance precision medicine in T-ALL, explore the identification of novel metabolic vulnerabilities, and discuss the potential of targeted therapies and dietary interventions to optimize treatment outcomes.

PURPOSE: The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC).

Patients aged ≥50 years with r/r MCL had superior OS and lower nonrelapse mortality 1 year after receiving brexu-cel compared with alloHCT. However, the long-term PFS and OS are similar for both treatments. Individual risk-benefit evaluation is essential to guide optimal treatment decisions.

Abstract: Journal Journal of Clinical Oncology.

Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.

We discuss the mechanisms of AML immune evasion including loss or downregulation of MHC class I and II, reduced TRAIL receptor expression, inhibitory metabolite production, inhibitory ligand expression, impaired proinflammatory cytokine production, and AML niche alterations.

PURPOSE: To update the ASCO evidence-based recommendations on the use of sentinel lymph node biopsy (SLNB) in patients with early-stage breast cancer treated with initial surgery.

Abstract: To identify nasopharyngeal carcinoma (NPC)-relevant T cell receptors (TCRs), we profile the repertoires of peripheral blood TCRβ chains from 228 NPC patients, 241 at-risk controls positive for serum Epstein-Barr virus (EBV) VCA-IgA antibody, and 251 seronegative controls. We develop a TCR-based signature (T-score) based on 208 NPC-enriched CDR3β sequences, which accurately diagnoses NPC in both the original and independent validation cohorts. Notably, a higher T-score, associated with a shorter time interval to NPC diagnosis, effectively identifies early-stage NPC among EBV-seropositive at-risk individuals prior to clinical diagnosis. These NPC-enriched TCRs react against not only EBV-specific antigens but also non-EBV antigens expressed by NPC cells, indicating a broad range of specificities. Moreover, the abundance of NPC-enriched CD8 T cells in blood correlates with the infiltration of non-exhausted T cell counterparts in tumors and predicts prolonged survival, suggesting that these NPC-enriched T cells have significant potential for disease monitoring and therapeutic applications.

No abstract available

Our investigation of the SOCS1 pathway in AML and T-cell interactions provides insights into potential mechanisms of resistance of AML to allogeneic hematopoietic stem cell transplantation and demonstrates the potential of targeting SOCS1 and its downstream mediators to enhance antileukemic T-cell activity. See related commentary by Fry, p. 157.