Anti-programmed Cell Death Protein Research Articles

Single-cell RNA sequencing analysis of peripheral blood mononuclear cells in PD-1-induced renal toxicity in patients with lung cancer

BackgroundAlthough the patient survival rate for many malignancies has been improved with immune checkpoint inhibitors (ICIs), some patients experience various immune-related adverse events (irAEs). IrAEs impact several organ systems, including the kidney. With anti-programmed cell death protein 1 (PD-1) therapy (pembrolizumab), kidney-related adverse events occur relatively rarely compared with other irAEs. However, the occurrence of AKI usually leads to anti-PD-1 therapy interruption or discontinuation. Therefore, there is an urgent need to clarify the mechanisms of renal irAEs (R-irAEs) to facilitate early management. This study aimed to analyse the characteristics of peripheral blood mononuclear cells (PBMCs) in R-irAEs.MethodsPBMCs were collected from three patients who developed R-irAEs after anti-PD-1 therapy and three patients who did not. The PBMCs were subjected to scRNA-seq to identify cell clusters and differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses were performed to investigate the most active biological processes in immune cells.ResultsFifteen cell clusters were identified across the two groups. FOS, RPS26, and JUN were the top three upregulated genes in CD4+ T cells. The DEGs in CD4+ T cells were enriched in Th17 differentiation, Th1 and Th2 cell differentiation, NF-kappa B, Nod-like receptor, TNF, IL-17, apoptosis, and NK cell-mediated cytotoxicity signaling pathways. RPS26, TRBV25-1, and JUN were the top three upregulated genes in CD8+ T cells. The DEGs in CD8+ T cells were enriched in Th17 cell differentiation, antigen processing and presentation, natural killer cell-mediated cytotoxicity, the intestinal immune network for IgA production, the T-cell receptor signalling pathway, Th1 and Th2 cell differentiation, the phagosome, and cell adhesion molecules.ConclusionsIn conclusion, R-irAEs are associated with immune cell dysfunction. DEGs and their enriched pathways identified in CD4+ T cells and CD8+ T cells play important roles in the development of renal irAEs related to anti-PD-1 therapy. These findings offer fresh perspectives on the pathogenesis of renal damage caused by anti-PD-1 therapy.

Steroid-Refractory Myocarditis Induced by Immune Checkpoint Inhibitor Responded to Infliximab: Report of Two Cases and Literature Review.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand(PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4(CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events(irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α.

Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy

BackgroundTumourigenesis in right-sided and left-sided colons demonstrated distinct features.ObjectiveWe aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis.DesignSingle-cell and spatial...

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer

BackgroundSitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).MethodsEligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1–naïve or –treated HCC and anti-PD-(L)1–naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).ResultsAt data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7–36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7–49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4–30.2) with anti-PD-(L)1–naïve HCC, 9.5% (95% CI 1.2–30.4) with anti-PD-(L)1–treated HCC, and 16.1% (95% CI 5.5–33.7) in patients with anti-PD-(L)1–naïve GC/GEJC.ConclusionsSitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

An atlas of genetic effects on cellular composition of the tumor microenvironment.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

Safety and efficacy of immunotherapy using a double-dose regimen in advanced non-small cell lung cancer (NSCLC): results of IDEE study.

Pembrolizumab 400 mg every six weeks (Q6W) and nivolumab 480 mg every four weeks (Q4W) are used since 2020 and the coronavirus disease 2019 (COVID-19) pandemic. This recommendation relied on pharmacokinetic and pharmacodynamic models. The objective of the IDEE (Immunothérapie Double dose Etendue: Experience bretonne) study is to determine the safety and efficacy of this treatment regimen in real life conditions. We conducted an observational, retrospective, multicentric study including 117 patients with advanced non-small cell lung cancer (NSCLC) who received pembrolizumab Q6W or nivolumab Q4W between March 2020 and March 2021. The median age was 67 years, 68% were men with predominantly lung adenocarcinoma. The median time to double-dose regimen failure (TDDF) was 9.2 months. The survival rate at 12 months was 79%. TDDF was not influenced by sex, line of treatment, pathologic subtypes or anti-programmed cell death protein 1 (PD-1) antibody. There was no correlation between TDDF and duration of prior exposition to immunotherapy before switching. Sixty-eight patients experienced double-dose treatment failure, 28% because of toxicity including five definitive discontinuations. Five grade ≥3 immune-adverse events were reported included two cases of pneumonitis, all responding to corticosteroid therapy. Our multicentric cohort supports the feasibility of pembrolizumab Q6W and nivolumab Q4W for patients with advanced NSCLC. There is no warning signal regarding safety neither efficacy in our real-life data.

PD-1 blockade combined with chemotherapy and bevacizumab in DNA mismatch repair-proficient/microsatellite stable colorectal liver metastases.

Single-agent immunotherapy is less effective in patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). Whether pMMR/MSS mCRC patients benefit from combination immunotherapy remains unclear. This study aimed to evaluate the efficacy and safety of anti-programmed cell death protein 1 (PD-1) therapy combined with chemotherapy and bevacizumab in pMMR/MSS colorectal liver metastases (CRLM) patients. A total of 12 patients with pMMR/MSS CRLM treated at The Sixth Affiliated Hospital of Sun Yat-sen University were enrolled. All patients were treated with at least 4 doses of PD-1 monoclonal antibody combined with chemotherapy and bevacizumab as neoadjuvant/adjuvant therapy. A total of 10 of the 12 patients received the combined therapies before primary tumor resection; the disease control rate (DCR) was 100% (10/10), and the objective response rate (ORR) was 70% (7/10). The ORR of liver metastases was 75% (9/12). Pathological complete response (pCR) was achieved in 1 primary tumor patient and 2 patients with hepatic lesions. A total of 5 patients underwent simultaneous resection of the primary tumor and liver metastases; 9 patients underwent microwave ablation for liver metastases. A total of 7 patients were assessed as having no evidence of disease (NED) with a median progression-free survival (PFS) interval of 9.2 (1.5-15.8) months after multimodality treatments for both primary and metastatic lesions. No severe immune-related adverse events (irAEs) and operational complications were observed. PD-1 blockade combined with chemotherapy and bevacizumab might be safe and effective for patients with pMMR/MSS CRLM. This treatment strategy might lead to better tumor regression and a higher chance of achieving NED.

Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune...

Differentially expressed circular RNA profiles and comprehensive analysis of circRNA-miRNA-mRNA regulatory network in microsatellite instability-high endometrial cancer

The clinical benefit of anti-programmed cell death protein 1 (PD-1)-based immunotherapy among patients with microsatellite instable (MSI) endometrial cancer (EC) precedes that of microsatellite stable (MSS) EC, the mechanisms of which have not been fully understood. Circular RNAs (circRNAs) were reported to modulate immune evasion in several types of malignancies, while their roles in the immune regulation in EC remain largely unknown. Here, we conducted circRNA array analysis and mRNA-Sequencing of 10 MSI EC samples and 10 MSS EC samples and identified 1083 differentially expressed circRNAs (DE-circRNAs) and 864 differentially expressed mRNAs, based on which we constructed a circRNA-miRNA-mRNA comprehensive network consisting of 35 DE-circRNAs, 56 predicted miRNAs and 24 differentially expressed mRNAs. Finally, we confirmed hsa_circ_0058230 being positively correlated with CD8+ T cells infiltration, suggesting that it might take a part in anti-tumor immunity in EC.

Safety and tolerability of immune checkpoint inhibitors in people with HIV infection and cancer: insights from the national prospective real-world OncoVIHAC ANRS CO24 cohort study

BackgroundImmune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH).MethodsThe ANRS CO24...

Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma

BackgroundImmune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and...

Tocilizumab in the treatment of steroid refractory immune-related hepatotoxicity: a case series and review of the literature.

With the widespread use of immune checkpoint inhibitors, management of immune-related adverse effects specific to these treatments became an important research era in patient management. Among these, immune-related hepatotoxicity (IRH) is an adverse event that can be fatal. While the first-line treatment of IRH is well established, there is still no consensus regarding the management approach for steroid-refractory, severe IRH. Here, we report four patients with metastatic melanoma who developed IRH during antiprogrammed cell death protein-1 plus anticytotoxic T-lymphocyte-associated protein-4 combination therapy and review of the literature. All of our patients were steroid-refractory and were successfully treated with tocilizumab. Given the rapid improvement in liver enzymes and patient's clinical status with tocilizumab, this treatment should be prioritized in steroid-refractory IRH.

Regorafenib in patients with pretreated advanced melanoma: a single-center case series.

Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF V600 mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab ( n = 5), trametinib ( n = 8), binimetinib ( n = 2), encorafenib ( n = 1), dabrafenib/trametinib ( n = 9), or encorafenib/binimetinib ( n = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF V600mut patient treated with REGO plus anti-PD-1, and a NRASQ61mut patient treated with REGO plus a MEK inhibitor. Common grade 3-4 treatment-related adverse events included arterial hypertension ( n = 7), elevated transaminase levels ( n = 5), abdominal pain ( n = 3), colitis ( n = 2), anorexia ( n = 1), diarrhea ( n = 1), fever ( n = 1), duodenal perforation ( n = 1), and colonic bleeding ( n = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1-14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0-33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF V600mut patients.

Total-Body Dynamic Imaging and Kinetic Modeling of [18F]F-AraG in Healthy Individuals and a Non-Small Cell Lung Cancer Patient Undergoing Anti-PD-1 Immunotherapy.

Immunotherapies, especially checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) antibodies, have transformed cancer treatment by enhancing the immune system's capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. 18F-arabinosyl guanine ([18F]F-AraG) is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by noninvasive quantification of immune cell activity within the tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of [18F]F-AraG as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of 4 healthy subjects and 1 non-small cell lung cancer patient who was scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection was used to analyze tracer kinetics in various organs. Additionally, 7 subregions of the primary lung tumor and 4 mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess the reliability of kinetic parameter estimation. Correlations of the SUVmean, the tissue-to-blood SUV ratio (SUVR), and the Logan plot slope (K Logan) with the total volume of distribution (V T) were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between K Logan and SUVR with V T, suggesting that they can be used as promising surrogates for V T, especially in organs with a low blood-volume fraction. Moreover, practical identifiability analysis suggested that dynamic [18F]F-AraG PET scans could potentially be shortened to 60 min, while maintaining quantification accuracy for all organs of interest. The study suggests that although [18F]F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response after therapy. Although SUVmean showed variable changes in different subregions of the tumor after therapy, the SUVR, K Logan, and V T showed consistent increasing trends in all analyzed subregions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of [18F]F-AraG dynamic imaging as a noninvasive biomarker for quantifying the immune response to immunotherapy in cancer patients. Promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.

Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study

IntroductionEftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+/CD8+) activation and helps overcome resistance to programmed cell death protein 1/programmed death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC. MethodsAfter confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary end point was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary end points included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory end points included tumor growth kinetics and predefined subgroup analyses. Programmed death-ligand 1 tumor proportion score was assessed centrally. ResultsThirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low/negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response rate and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. ConclusionsEfti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment

BackgroundTG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify...

Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model.

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.

Pt-Te-Nanorod-Based Photothermal Chemokine Immunotherapy for All Stages of Cancer via Adaptive and Innate Immunity.

The chemokine (C-X-C) motif ligand 9 (CXCL9) is one of the lymphocyte-traffic-involved chemokines. Despite the immunotherapeutic potential of CXCL9 for recruiting effector T cells (cluster of differentiation 4+ (CD4+) and CD8+ T cells) and natural killer cells (NK cells) around the tumors, practical applications of CXCL9 have been limited because of its immune toxicity and lack of stability in vivo. To overcome these limitations, we designed and synthesized Pt-Te nanorods (PtTeNRs), which exhibited excellent photothermal conversion efficiency with stable CXCL9 payload characteristics under the physiological conditions of in vivo environments. We developed a CXCL9-based immunotherapy strategy by utilizing the unique physicochemical properties of developed PtTeNRs. The investigation revealed that the PtTeNR-loaded CXCL9 was effectively accumulated in the tumor, subsequently released in a sustained manner, and successfully recruited effector T cells for immunotherapy of the designated tumor tissue. In addition, a synergistic effect was observed between the photothermal (PT) therapy and antiprogrammed cell death protein 1 (aPD-1) antibody. In this study, we demonstrated that PtTeNR-based CXCL9, PT, and aPD-1 antibody trimodal therapy delivers an outstanding tumor suppression effect in all stages of cancer, including phases 1-4 and tumor recurrence.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Tumor Microenvironment Reprogramming Improves Nanomedicine-Based Chemo-Immunotherapy in Sarcomas

Abstract Sarcomas are a heterogeneous group of rare cancers that originate in soft tissues or bones. Their complexity and tendency for metastases make treatment challenging, highlighting the need for new therapeutic approaches to improve patient survival. The difficulties in treating these cancers primarily stem from abnormalities within the tumor microenvironment (TME), which leads to reduced blood flow and oxygen levels in tumors. Consequently, this hampers the effective delivery of drugs to tumors and diminishes treatment efficacy despite higher toxic doses of chemotherapy. In this study, we tested the mechanotherapeutic ketotifen combined with either pegylated liposomal doxorubicin (PLD) or pegylated liposomal coencapsulated alendronate–doxorubicin (PLAD) plus anti–programmed cell death protein 1 antibody in mouse models of fibrosarcoma and osteosarcoma. We found that ketotifen successfully reprogrammed the TME by reducing tumor stiffness and increasing perfusion, proven by changes measured by shear-wave elastography and contrast-enhanced ultrasound, respectively, and enhanced the therapeutic efficacy of our nanomedicine-based chemo-immunotherapy protocols. Furthermore, we observed a trend toward improved antitumor responses when nano-chemotherapy is given alongside anti–programmed cell death protein 1 and when the immunomodulator alendronate was present in the treatment. We next investigated the mechanisms of action of this combination. Ketotifen combined with nanomedicine-based chemo-immunotherapy increased T-cell infiltration, specifically cytotoxic CD8+ T cells and CD4+ T helper cells, and decreased the number of regulatory T cells. In addition, the combination also altered the polarization of tumor-associated macrophages, favoring the M1 immune-supportive phenotype over the M2 immunosuppressive phenotype. Collectively, our findings provide evidence that ketotifen-induced TME reprogramming can improve the efficacy of nanomedicine-based chemo-immunotherapy in sarcomas.