IL7R expression

IL7R plays a critical role in shaping TME diversity across cancer types and holds promise as a relevant biomarker for predicting immunotherapy benefits.

Our findings underscore a significant causal relationship between immunophenotypes and endometrial cancer in bidirectional MR analyses. Notably, the CM CD4+%T immunophenotype emerged as potentially crucial in endometrial cancer development.

This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options.

Lusvertikimab-mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, Lusvertikimab may represent a novel immunotherapy option for any CD127-positive ALL, particularly in combination with standard-of-care polychemotherapy.

When applied to HSPCs further induced to differentiate into T cells in an Artificial Thymic Organoid system, our gene editing strategy overcame the T cell developmental block observed in IL7R-SCID patients, while promoting full maturation of T cells with physiological and developmentally regulated IL7R expression. Finally, genotoxicity assessment of the CRISPR/Cas9 platform in HSPCs using biased and unbiased technologies confirmed the safety of the strategy, paving the way for a new, efficient, and safe therapeutic option for IL7R-SCID patients.

This information can provide real-time guidance to patients, families, and providers on expectations. Additionally, CD4+CD127+ cells in the starting material appear to be necessary to overcome high disease burden, suggesting the importance of optimized manufacturing to expand this favorable cell subset.

Our data demonstrate T-bet overexpression improves CD28-costimulated CAR T cell expansion but does little to augment long-term responses and diminishes features associated with capacity for self-renewal. In contrast, T-bet overexpression boosts the potency of 4-1BB-costimulated CAR T cells without impairing persistence, resulting in improved overall efficacy of 4-1BB-costimulated CAR T cell therapies.

In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration...For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7RALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3KALT)...Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%)...A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

1x106 CAR T cells (figure 2). Conclusions These data suggest that LYL119, which combines c-Jun overexpression, NR4A3 KO, Epi-R protocol, and Stim-R technology, can limit exhaustion, maintain stem-like features, and has potential to provide effective and durable CAR T-cell antitumor activity in patients with ROR1+ solid tumors.

In agreement with these findings, the cytokine binding CD127 was increased in patients with durable response to ICI (p<0.05, Student’s t-test). In this pilot study using pre-treatment biopsies from independent melanoma cohorts, we report that CD127 is associated with a favorable response to immune-checkpoint therapy. A marker of immune-checkpoint therapy response could help improve care for melanoma patients by informing the provision of optimal therapies and minimizing side-effects.

Thus, TCF1CD4 T cells function as disease stem cells and promote chronicity and autonomy of autoimmune tissue inflammation. Remission-inducing therapies will require targeting stem-like CD4 T cells instead of only effector T cells.

PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1, further promoting the downstream JAK1/STAT5/Bcl-2 pathway. Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

The role of CAFs and the mechanisms affecting NK cells require further research. The present project will enhance our understanding of the TME components and the antitumor response in an understudied disease.

These results suggest the potential application in routine practice of high-dimensional spectral immune profile asa biomarker for clinical monitoring. Further investigation is ongoing to increase the study cohort and address the clinical benefit of its use in a combined liquid biopsy approach and as a tool to informed- treatment selection.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Altogether, this study provides valuable information to optimize translation of JAKi and venetoclax to clinics for T-ALL patients with relapse who need therapeutics to bridge to transplant. This treatment protocol may benefit to a larger group of patients who may be selected with an easily applicable flow-cytometry-based companion test. IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T- ALL patients eligible to JAKi up to nearly ~70% of T-ALL.

Conversely, mutants were more sensitive to venetoclax than expressers. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

In fact, ADCP levels induced by OSE-127 treatment in vitro correlated with its capacity to reduce ALL blasts in the blood of PDX mice in vivo. Altogether, through its dual mode of action, OSE-127 may represent a powerful novel immunotherapy option for ALL patients, including cases with dysregulated IL7R signaling, particularly in combination with standard of care polychemotherapy.

Using an endogenous T cell receptor (TCR) sequence as a ‘barcode’, we followed individual T cell clonotypes at the single-cell level from pre-manufacture apheresis and infusion products to tumor-involved lymph node and blood at peak and late expansion in 22 adult patients with relapsed or refractory large B cell lymphoma (LBCL) or acute lymphoblastic leukemia (ALL) treated with axicabtagene ciloleucel, an FDA-approved CD19-CAR T cell immunotherapy, or bispecific CD19/CD22 CAR T cells on an investigator-initiated trial (NCT03233854)...These analyses pinpoint the identities of source T cells and infusion CAR T cells with properties impacting efficacy, and also identify ligand-receptor pairs that could be modulated to enhance CAR T cell response in the tumor at the genetic or pharmacological level. This work was supported in part by the Parker Institute for Cancer Immunotherapy, California Institute for Regenerative Medicine, Kite Pharma, and Stanford Cancer Institute.

P=N/A, N=83, Not yet recruiting, Rania Abdeltwab Abdelazeim

They also displayed a lower expression of the exhaustion markers PD1 and TIM3. Better understanding of how signal integration in a bicistronic construct relates to CAR T cell function may have future implications in helping to predict clinical outcomes after CAR manufacturing, and the ability to harness knowledge of signal integration has the potential to aid in the design of future CAR T cell products.

We comprehensively describe the immune microenvironment in the BM of MM patients around ASCT and identify a pre-existing CD4 T cell subset that is associated with depth of response to ASCT. Further studies are required to better define the role of this population in modulating the response to melphalan. Prospective follow up of patients is ongoing to assess which clusters are associated with progression-free and overall survival.

We previously reported high preclinical efficacy of OSE‑127 in BCP-ALL patient derived xenograft (PDX) models of different cytogenetic backgrounds (Lenk and Baccelli et al...Finally, we conducted a phase2-like PDX overt leukemia study testing OSE‑127 alone or in combination with Dexamethasone/Vincristine/PEG-Asparaginase chemotherapy employing PDX samples with high CD127 expression (6 BCP-ALL and 3 T-ALL-PDX samples with >50% CD127+ cells in flow cytometry analysis)...and D.M.S. share senior authorship

All 12 MB-CART2019.1 DPs exhibited a consistent and reproducible expansion profile, high CD4:CD8 ratio, high TCM proportion and low expression of exhaustion markers. Increased proliferative ability in the DP, higher Cmax, as well as maintaining higher levels of TCM during in vivo expansion were characteristically elevated parameters of pts with CR. Other product characteristics, e.g. CD4:CD8 ratio or number of infused T-cells, were not significantly associated with in vivo performance.

Furthermore, inhibition of BMP2 pathway significantly blocked the emergence of Reg-Vδ2 cells and enhanced the anti-AML immunity in humanized mice. These findings not only provide a novel insight into the mechanisms of immunosuppression in the context of leukemia, but also suggest potential targets for the treatment of AML and other hematopoietic malignancies.

P2, N=200, Completed, AIO-Studien-gGmbH | Active, not recruiting --> Completed

Conclusions Altogether, our data show that IL7R pathway expression in TILs and tumor-specific Tcell clonotypes are predictive of long-term ICI clinical response. Redirecting IL7 on PD1+Tcells provides stemness, proliferative and survival signals to tumor-specific Tcells capable to induce durable response.

DATA AVAILABILITY: Data are available upon reasonable request. The RNA-seq dataset comparing the transcriptomes of control and calcipotriol-treated GL261 tumors is available from the corresponding author upon request.

Our data suggest that PRGs, especially CASP8, showed strong associations with patient outcomes and TICs in BLCA. If validated, these results could potentially aid in the prognostication and guide treatment in BLCA patients.

The current data suggested that insufficient IL-7 secretion might contribute to CD8 T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.

A significant association was found between the transcript level of IL7R and the percentage of CD8 T cells in nucleated cells (P=0.015) but not CD4 T cells (P=0.47). Low IL7R transcript level of bone marrow at diagnosis predicted relapse in t(8;21) AML, which might be caused by the difference in the amount, status and function of T cells.

Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.

Tracking TCR clonotypes at the single cell level reveals in two patients that peptide-specific long-lasting CD8 T cells acquire an effector memory phenotype that associates with cell cycle-related genes (CCNA2 and CDK1), and are characterized by high expression of IL7R, SELL, and NOSIP along with a later stage promotion of the AP-1 transcription factor network (5 years or more past vaccination). We conclude that effective anti-tumor immunity is governed by potentially proliferative memory T cells, specific to cancer antigens.

Circ_MTM1 could serve as a promoter in HBV-related LF through miR-122-5p/IL7R axis.

Conclusion In sum, our comprehensive analyses revealed fundamentally different mechanisms driving either type-1 or type-2 T-ALL relapse and indicate that differential capacities of disease evolution are already inherent to the molecular setup of the initial leukemia. Leukemias of patients with type-1 relapses were often characterized by upregulation of the IL7R pathway, whereas type-2 relapses were characterized by (i) an enrichment of TAL-1 fusion, (ii) and of constitutional mutations in CPG, (iii) divergent genetic and epigenetic remodeling, and (iv) an enrichment of somatic hypermutator phenotypes.

A comparative bioinformatics analysis of 15 bone marrow and 10 peripheral blood samples from Hispanic B-ALL patients collected by the TARGET program, corroborated the genes observed, except for PIK3CG. We conclude the Mexican and the Hispanic B-ALL patients studied present common driver alterations and histotype-specific mutations that could facilitate risk stratification and diagnostic accuracy and serve as potential therapeutic targets.

Most neoantigen-reactive CD4 T cells from a patient with bile duct cancer also exhibited an exhausted phenotype but with overexpression of HOPX or ADGRG1 while lacking IL7R expression. Thus, neoantigen-reactive T cells infiltrating gastrointestinal cancers harbor distinct transcriptomic signatures, which may provide new opportunities for harnessing these cells for therapy.

Our results suggest that IL7R inhibits tumor growth by regulating the proportion of immune infiltrating cells in the tumor immune microenvironment. IL7R could be a beneficial prognostic marker in patients with lung adenocarcinoma and has great potential in immune therapy.

Using an approach called reverse fate mapping, we followed individual T-cell clones at the single-cell level from pre-manufacture apheresis to the infusion product, tumor-involved lymph node, and blood at peak and late expansion in 12 adult patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel, an FDA-approved CD19-CAR T-cell immunotherapy...These analyses pinpoint the molecular mechanisms that could be modulated to rationally steer CAR T-cell differentiation trajectories at the genetic or pharmacological level. This work was supported in part by the Parker Institute for Cancer Immunotherapy, California Institute for Regenerative Medicine, Kite Pharma, and Stanford Cancer Institute.

Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

Associations of phenotypes with clinical variables, and post-treatment phenotypes will be described in detail at the meeting. Our results detail new immunotherapy and biomarker research targets, and suggest novel strategies for combination therapies.