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nCounter® PanCancer IO 360™ Panel

Combination therapy with poly-ICLC, especially through IT route, and anti-PD-1 provides significantly greater antitumor effects than anti-PD-1 monotherapy in syngeneic mouse models of HCC.

Conclusions Overall, these preliminary data reveal a potential crosstalk between deregulated cancer cell proliferation and MARCO+Mφs in mediating disease progression and ICI resistance of ccRCC. Mechanistic experiments will be performed to confirm this assumption and to test whether targeting cancer cell-deregulated proliferation (e.g. by FDA-approved CDK4/6-TAs) could reshape ccRCC-mediated Mφ polarization and improve ICI efficacy.

These findings underscore the significance of pre-treatment systemic inflammation (e.g. serum TNFa levels), product T cell phenotype, TMTV, CAR T-cell expansion, tumor IFN signaling and FLIPI as independent factors associated with clinical outcomes in patients with r/r FL treated with axi-cel. These results offer insights into mechanisms of resistance and toxicity, risk stratification, combination therapy and development of next-generation CAR-T therapy for patients with r/r FL.

We then profiled a wet-lab cohort of 37 FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoString Technologies, San Diego, CA). This study provides evidence that FLT3 mutational status is associated with a unique T-cell activation profile and AML maturation state, and that T/NK cell-associated genes correlate with response to FLT3i. Our RNA metric of FLT3 mutational status could be utilized to refine patient stratification in future clinical trials. S.R.

Background TOPACIO was a phase I/II study evaluating the PARP inhibitor (PARPi) niraparib in combination with the anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic triple-negative breast cancer (TNBC, n=55), irrespective of BRCA mutation status. The study protocol and/or other relevant documents received central approval by the Dana-Farber institutional review board and/or relevant competent authorities at each site. All patients supplied written informed consent for their participation in the study.

Methods Transcriptomic analysis of baseline or on-treatment (PARPi, talazoparib) biopsies from patients with BRCA-associated TNBC from the TALAVE clinical trial (NCT03964532) were assessed using the NanoString-IO360™ and Digital Spatial Profiling (DSP) platforms. Tumor-bearing mice (K14-Cre/Brca1f/f/p53f/f ) were treated with vehicle or PARPi (olaparib) for 5 days and gene expression profiling, flow cytometry and mass spectrometry-based metabolome analysis were utilized to determine the metabolic profile of tumors. To inhibit lipid synthesis, mice were treated with fatostatin (SREBP1 inhibitor) or denifanstat (FASN inhibitor)...Ethics Approval The present study was approved by BWH CMM IACUC, protocol number is 2020N000142 and by Dana-Farber Cancer Institute, protocol number is 20–627. Study drugs were provided by Pfizer, as part of an alliance between Pfizer and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Salus IRB, Protocol STC15-22101. All patients gave informed consent before participation.

Methods Gene profiling analysis was performed using NanoString IO360 panel from PBMCs of melanoma patients treated with anti-PD1 (pembrolizumab/nivolumab) in both clinical setting (adjuvant and first line therapy). Conclusions In this retrospective study, we identify gene signatures model associated with the onset of skin toxicities related to anti-PD1 treatment in stage III/IV unresectable and resected stage III melanoma patients. Further investigations are needed in order to validate the signature in an independent dataset.View this table:View inline View popup Download powerpoint Abstract 1172 Table 1 Patient characterisitics

© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

These findings provide valuable insights into the temporal dynamics and immune responses within the tumour microenvironment following TRT and ICI combination therapy. Based on these results, future research should prioritize investigating the role of specific immune cell subsets and optimizing treatment application, particularly focusing on dosing and timing strategies.

We then screened a cohort of FLT3-mut AML patients treated either with Midostaurin plus chemotherapy (M) or Gilteritinib (G) at Bologna Hematology Institute by using the PanCancer IO 360 Panel (NanoS-tring GEA). This study highlights how FLT3 mutational status is associated with T-Cell activation and AML maturation state. Differences in immune transcriptomic profile impact on FLT3i response.

By combining a spatial approach with expression data for immune-related pathways and associated overall survival data, we provide an effective strategy and workflow for the identification of prognostic biomarkers in OSCC.

All LELC-B cases showed high TMB of 39 Mut/Mb (IQR 29-66). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD1/PD-L1 and making ICI a promising treatment option.

Patients with a >6 month OS had tumors with elevated NK cell gene signatures compared to patients with poor survival. Further, the analysis revealed numerous differentially expressed genes based on patient age, tumor location, response to treatment, and OS which warrant future validation for assessing relationship with clinical outcomes in patients.

In our study, we have identified a favorable TiME for L-DFS rPDAC Pts under PO Gem-nabPac CTX. We further present minimal immune-related liquid biomarker signatures based on mELISA and ML for early prediction of Gem-nabPac CTX success in PO and A treatment settings, or for rPDAC Pts in general.

The neoadjuvant platform offers unique insights into the tumor microenvironment and dynamics of the immune response over time. Our analysis reveals consistencies with previously published biomarkers associated with response to immune checkpoint inhibitors (IFN- γ) and provides insights into new biomarkers associated with response to nivo + rela, specifically B7-H3. Taken together, this work expands our insights into who may benefit from nivo + rela and provides insights into potentially actionable strategies to personalize tx approaches.

In our study, we have identified a favorable TiME for L-TTF mPDAC Pts (2nd line CTX) showing CD8 T cell inflamed ("hot") tumor tissues prior to 2nd line CTX. We further present a 9-marker liquid biomarker panel including 9 flow cytometry PBMC population gates for early prediction of 2nd line nal-IRI/5-FU/FA therapy success in mPDAC Pts. With our findings, we aim to advance the personalized treatment of mPDAC Pts e.g. by additionally exploring the potential for immunotherapy in patients with a positive marker signature.

Our preliminary data suggest that the immune-related markers signature in the healthy peritumoral mucosa might be useful for predicting relapse after adjuvant therapy in rectal cancer patients. Moreover, relapsing patients showed lower stimulation of macrophages and lymphocytes, thus suggesting that impaired immune surveillance might influence adjuvant therapy outcomes. Sampling healthy mucosa might help the decision-making about adjuvant therapy after surgery for rectal cancer.

The CD8+T cells infiltrate more in the WNT subtype MB than other subtypes. The mechanism may be related to the activation of CXCL11-CXCR3 chemokine system, and the patients with more infiltration of CD8+T cells in tumor have better prognosis. This finding may provide the necessary clinicopathological basis for the regulatory mechanism of CD8+T cells infiltration in MB, and give a new potential therapeutic target for the future immunotherapy of MB.

Finally, combinatorial treatment with an AREG neutralizing antibody and carboplatin led to a synergistic reduction of cell viability in HGSOC cell lines OVCAR8 and PEA2. Overall, this study demonstrates AREG's ability to modulate cytotoxic responses within the OTIME and highlights its role as a novel HGSOC immune target.

Induction therapy consistedof methotrexate, vincristine, procarbazine (MVP) with (40...1%) rituximab (R-MVP)... We observed a significant proportion of "high-risk" PCNSL characterized by dismal prognosis and tumorupregulation of immune checkpoints TIGIT and HAVCR2, supporting immune evasion as a disease mechanism. This represents a potential avenue for integrating immunotherapy into existing treatment regimens.

With the limitation of the low number of patients analysed, this study suggests that differences in immunetranscriptomic profile are associated with response to Aza-Ven in newly diagnosed unfit-for-chemotherapyAML patients. Some specific gene expression patterns are differentially shown at diagnosis in responders ascompared to refractory patients, while interesting and still unexplored pathways and signals, such as T-cellsactivation and priming, and antigen presentation, were described in responder patients during therapy andrelated to incoming relapse. Further studies on larger cohorts of patients are highly warranted to confirm ourpreliminary findings.

In this study, we have identified a favorable TiME for L-TTF (2nd line CTX) mPDAC patients showing CD8+-T cell inflamed ("hot") tumor tissues prior to 2nd line CTX. We further propose CXCR3+-CD8+ T cells as potential liquid biomarker for predicting 2nd line nal-IRI/5-FU/FA success.

We show that exercise training during NAC, which improves cardiorespiratory fitness, is associated with increased frequencies of TILs and maturity of TLS. These data suggest that exercise during NAC enhances the immune system possibly to be suitable for immunotherapy.

To our knowledge, this is the first longitudinal RNA analysis reported from pts treated with nivo+rela. BL immune features associated with major pathologic response include higher GES of B cells, CD45+ cells, CD8 T cells, and increased expression of TIGIT, IDO and IFN-y. Additionally, higher B7-H3 in non MPR pts may indicate a clinically actionable strategy for further evaluation.

Methods Gene profiling analysis was performed using NanoString IO360 panel from PBMCs of pts with cutaneous melanoma treated with antiPD1 (pembrolizumab or nivolumab) in both clinical setting (adjuvant and first line therapy). Conclusions In this retrospective study, we identify gene signatures model associated with the onset of skin toxicities related to anti-PD1 treatment in stage III/IV unresectable and resected stage III melanoma pts. Further investigations are needed in order to validate the signature in an independent dataset.

In conclusion, we observed a convergence of both mutational and expression signatures on angiogenesis signaling pathways in our AS-B cases. The spatial transciptomic data revealed that AS-B was enriched for tumor-infiltrating macrophages and T-cells which might have implications on the role of immunotherapy.

We characterized the expression of CLDN6 across the different cohorts of OSCC samples and further investigated the relationship within the tumor immune microenvironment coupled to genes related to the prognosis of OSCC. A better understanding of the TME and gene expression profiling of OSCC tumors and the effect of smoking will allow us to tailor the treatment of patients to continue to improve outcomes.

Significant cytotoxicity was observed in 2 out of 10 patient tumors (20%) as a monotherapy and 4 out of 10 (40%) when used in combination with atezolizumab. These data support the prospects of NXI-101 as a first-in-class therapeutic for the treatment of NSCLC when used alone or in combination with an immune checkpoint inhibitor. Moreover, the findings highlight the PDOTS platform's substantial value in capturing patient-specific tumor response variability and providing robust support for the mechanistic evaluation of cancer therapeutics.

Lastly, IDO1 and PDL1-specific CD4+ T cell clones from melanoma patients treated with IO102-IO103 vaccine could selectively target cells differentially expressing IDO1 or PDL1.Our data collectively show that cells expressing IDO1 and PD-L1 represent distinct populations in the TME thus targetable by the IDO1-PD-L1 vaccination approach...These data are supported by ex vivo functional assays using target specific T cells from vaccinated patients. Altogether, our data support the use of a dual antigen approach to reduce the immunosuppression and enhance anti-tumor effect.

GeoMx WTA panel provided an unbiased view of 18,000 protein-coding genes at specific TME regions. These counts were successfully mapped to the 12 ROIs on the tissue. A pseudo-TIS score was generated using the same 18 gene signature from the WTA panel for each ROI.

At baseline, most patients exhibited low CD8+ TIL, PD-L1 and TIS, with enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL, peritumoral CD8+ T cells and TIS. Four of 5 pts with negative predictive baseline biomarkers [CD8+TIL/PD-L1/TIS]low experienced pCRs supporting activity of IL12/anti-PD1 based regimens in this setting.

IL20RA and SOX10 represent potential biomarkers for TNBC risk that may serve as a stratification tool for NHB women. The results of this study have the potential to improve assessment and management of TNBC risk among NHB women, thereby contributing significantly to reducing health disparities in breast cancer outcomes.

Furthermore, the differences between the EAOC subtypes suggest distinct processes driving EC or CCC development from endometriotic lesions, with a more inflammatory signature in EC that may be promising for the development future therapeutic strategies. This study sheds light on immune dynamics in ovarian endometriosis and EAOC, offering potential avenues for future research.

Validation using immunohistochemistry further supported these findings. In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.

Our data offer a cellular and molecular insight into a case of clinical pseudoprogression observed during tolinapant treatment. Understanding pseudoprogression is important for clinical investigators and patients to ensure treatment with tolinapant, or other IAP antagonists, are not discontinued prematurely.

Two cohorts of FLT3-mut AML patients treated either with Midostaurin in combination with intensive chemotherapy (M cohort) as induction or Gilteritinib (G cohort) as salvage at Seràgnoli Hematology Institute of Bologna were enrolled. Conclusions. This study portrays evolutionary trajectories under FLT3i-containing regimens pressure and highlights novel preliminary differences in immune transcriptomic profile associated with FLT3i effectiveness.

The TIS (tumor inflammation signature) and IFN-γ signatures constitute predictive biomarkers to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

Patients were lymphodepleted with fludarabine and cyclophosphamide...Multi-modal analyses of WU-NK-101 highlight unique transcriptional and functional states, which could underpin in vivo potency and persistence. WU-NK-101 are currently being evaluated in a phase 1 study of R/R AML (#NCT05470140).

Image analysis revealed that TDB treatment induced T cell-mediated cytotoxicity in four patients, with sub-optimal TDB-induced cytotoxicity observed in two patients, highlighting intrinsic resistance mechanisms to TDB treatment and the need for greater mechanistic understanding. Notably, all patients' effector cells exhibited upregulation of CD69, a T cell activation marker, after 24 hours post-TDB treatment which was sustained for 72 hours. TDB treatment also led to the upregulation of CD25, starting at 24 hours and peaking 72 hours post-treatment.

Moreover, we acquired an additional dataset of pre-treatment immune-related gene expression profiling obtained from the BM of 30 flotetuzumab-treated (CD3 x CD123 bispecific antibody) refractory/relapsed (R/R) adult AML patients (NCT02152956; Vadakekolathu et al., 2020) for TIDE-based immune deconvolution (Jiang et al., 2018)...Lastly, for the first time, we identified TLS-like aggregates in the BM of AML patients, which have been associated with immunotherapy response in many cancers (Schumacher & Thommen, 2022). Additional studies to further characterize the function and relevance of these lymphoid aggregates are ongoing.

This study confirmed evolutionary trajectories often involving RAS pathway mutations as an intrinsic mechanism of resistance to Gilteritinib therapy. Of note, differences in immune transcriptomic profiles, involving mainly CD8+ T-Cells and NK-Cells, were associated with response, pointing to a previously unappreciated role of the immune system in mediating response to Gilteritinib.