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Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients ( N  = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies. In a phase 1 dose-escalation trial in patients with nine different types of solid tumors, MAGE-A4-specific T cells had an acceptable safety profile and exhibited an encouraging overall response rate in patients with synovial sarcoma.

BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

BackgroundLetetresgene autoleucel (lete-cel) is an investigational T-cell receptor therapy targeting the NY-ESO-1 cancer/testis antigen, which is highly expressed in synovial sarcoma (SyS) and myxoid (with or without round cell) liposarcoma (MRCLS). An integrated analysis of lete-cel efficacy and safety was conducted using pooled data from three single-arm trials of patients with advanced SyS and MRCLS.MethodsThe integrated efficacy and safety analysis included data from two pilot trials (NCT01343043, NCT02992743) and the pivotal IGNYTE-ESO trial (NCT03967223), plus an ongoing long-term follow-up study (NCT03391778). Eligibility: previously treated advanced (unresectable/metastatic) SyS or MRCLS, human leukocyte antigen (HLA)-A*02:01, *02:05, or *02:06-positive, NY-ESO-1 expression, baseline ECOG 0–1, and received any dose of lete-cel. Treatment-naïve patients (SyS, n=5) were excluded from the efficacy analyses. Response was assessed by independent review in all three studies. Key efficacy endpoints: overall response rate (ORR) per RECIST v1.1, best overall response, duration of response (DoR), time to response, disease control rate, progression-free survival (PFS), overall survival (OS) and persistence. Key safety endpoints: adverse events (AEs), serious AEs, AEs of special interest, deaths, laboratory assessments, and replication competent lentivirus. Data was pooled and outputs present combined data and subgroup analyses summarized by indication and overall.ResultsA total of 178 sarcoma patients were enrolled, of which 147 received lete-cel and were included in the pooled safety population (97 [66.0%] with SyS, 50 [34.0%] with MRCLS) and 142 were evaluable for efficacy. At baseline in the overall population, median age was 40.0 years (range, 10–73), 44.4% were female, and 92.3% were White; baseline characteristics were similar across SyS and MRCLS. Independent reviewer-assessed ORR was 43.0% (61/142) overall, 45.7% (42/92) in SyS, and 38.0% (19/50) in MRCLS (table 1). Median DoR and PFS in overall/SyS/MRCLS was 7.16/6.74/7.16 months and 5.29/4.04/7.69 months, respectively. Median OS was 20.50 months overall. The integrated safety analysis will be presented but to date, lete-cel treatment has a manageable safety profile consistent with T-cell therapy and lymphodepletion, including transient serious cytopenias, rash, and mild/moderate cytokine release syndrome.ConclusionsThe integrated analyses provide a comprehensive report of the efficacy and safety profile of lete-cel in the largest population to date. Efficacy as assessed by ORR, PFS, and OS was comparable across indications, further supporting the validity of lete-cel as an effective therapy for patients with advanced SyS and MRCLS.AcknowledgementsThis analysis was funded by Adaptimmune. Writing and editorial support was by Chloe Koulouris, PhD, of Envision Pharma, Inc. (Horsham, UK), funded by Adaptimmune.Trial RegistrationLete-cel pilot trial in SyS (CT.gov, NCT01343043) Lete-cel pilot trial in MRCLS (CT.gov, NCT02992743) Lete-cel phase 2 IGNYTE-ESO (CT.gov NCT03391778)Ethics ApprovalThis was a secondary analysis of existing clinical trial data and did not require ethical approval. Written informed consent was obtained from participants at the time each trial was conducted.Abstract 320 Table 1Integrated efficacy analysis outcomes from previously treated patients with SyS or MRCLS who received lete-cel treatment in interventional clinical trials (independent review)

Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this mode of RAS signaling. RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.

A multitude of epigenetic modifications are necessary for successful development throughout early life and are associated with a youthful, healthy epigenetic landscape, but age-related and environmentally induced epigenetic changes can cause a multitude of pathologies in adults [1,2,3,4]. Additional manuscript topics include, but are not limited to, embryonic development, differentiation, metabolic signaling, DNA methylation, histone modifications, miRNAs, transposable elements, and the epigenetic clock. [...]manuscripts regarding possible treatment targets and early intervention via the modification of these molecular mechanisms are also welcomed, e.g., [21].

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling. Competing Interest Statement The authors have declared no competing interest.