Efficacy Of Immune Checkpoint Inhibitors Research Articles

Efficacy and safety of apatinib plus immune checkpoint inhibitors and transarterial chemoembolization for the treatment of advanced hepatocellular carcinoma

PurposeThe evidence of apatinib plus immune checkpoint inhibitors (ICIs) and transarterial chemoembolization (TACE) for treating advanced hepatocellular carcinoma (HCC) is limited. This study aimed to compare the treatment efficacy and safety of apatinib plus ICIs and TACE with apatinib plus TACE in these patients.MethodsThis study retrospectively enrolled 90 patients with advanced HCC treated with apatinib plus TACE (A-TACE group, n = 52) or apatinib plus ICIs and TACE (IA-TACE group, n = 38).ResultsThe objective response rate was numerically higher in IA-TACE group compared with A-TACE group without statistical significance (57.9% vs. 36.5%, P = 0.055). Disease control rate was not different between groups (86.8% vs. 76.9%, P = 0.248). Progression-free survival (PFS) was improved in IA-TACE group compared with A-TACE group (P = 0.018). The median PFS (95% confidence interval) was 12.5 (8.7–16.3) months in IA-TACE group and 8.5 (5.6–11.4) months in A-TACE group. Overall survival (OS) was also prolonged in IA-TACE group compared with A-TACE group (P = 0.007). The median OS (95% confidence interval) was 21.1 (15.8–26.4) months in IA-TACE group and 14.3 (11.5–17.1) months in A-TACE group. By multivariate Cox regression model, IA-TACE was independently associated with prolonged PFS (hazard ratio = 0.539, P = 0.038) and OS (hazard ratio = 0.447, P = 0.025). Most adverse events were not different between groups. Only the incidence of reactive cutaneous capillary endothelial proliferation was higher in IA-TACE group compared with A-TACE group (10.5% vs. 0.0%, P = 0.029).ConclusionApatinib plus ICIs and TACE may be an effective and safe treatment for patients with advanced HCC, but further large-scale studies are needed for verification.

Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer

BackgroundIn triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism.MethodsWe used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1.ResultsHN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions.ConclusionsCollectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Immune Checkpoint Inhibition-related Neuroinflammation Disrupts Cognitive Function.

Despite the superior therapeutic efficacy of immune checkpoint inhibition (ICI) for cancers, its undesired effects on brain function are not fully understood. Here, we demonstrate that combination ICI elevates neuroinflammation, activates microglia, leading to detrimental neurodegenerative and neurocognitive sequelae.

Learning About and Living With Toxicity: A Qualitative Study of Patients Receiving Immune Checkpoint Inhibitors For Melanoma or Lung Cancer and Their Caregivers.

Immune checkpoint inhibitors (ICIs) have revolutionized treatment for melanoma and lung cancer and are in widespread use. This study aims to describe how patients and caregivers learn about ICI toxicities and their perceptions and experiences of toxicity. We conducted a qualitative study of 42 patients with advanced non-small cell lung cancer (NSCLC; n = 16) or melanoma (n = 26) who were initiating or discontinuing an ICI and their caregivers (n = 9). We conducted in-depth interviews to explore patients' and caregivers' experiences learning about and living with ICI side effects. We audio-recorded the first oncology visit after enrollment. We used a framework approach to code interview and visit transcripts and synthesized codes into themes. The median age of patients was 67; 68% were male. Themes of participant interviews and clinician-patient dialogue included: i) Patients initiating an ICI received extensive information about side effects, which some patients found overwhelming or scary and difficult to absorb; ii) Patients who were deterred by fear of toxicity ultimately proceeded with treatment because of oncologist encouragement or the sense of no alternative; iii) participants found hope in the association between toxicity and ICI efficacy; iv) caregivers helped patients navigate the deluge of information and uncertainty related to ICIs. Participants suggested ways to improve ICI side effect education, such as incorporating patient stories. Patients perceived that ICI toxicity counseling was overwhelming yet were encouraged by oncologists' reassurance that serious side effects were manageable and by the framing of toxicity as a sign of efficacy. We identified opportunities to improve communication of ICI risks and benefits.

Outcomes of adjuvant immune checkpoint inhibitor therapy in melanoma: a retrospective study

ABSTRACT Background Adjuvant treatment of malignant melanoma has improved the outcomes for patients. However, real-world data on efficacy and safety are limited. We investigated outcomes of melanoma patients treated with adjuvant immune checkpoint inhibitors (ICI) in the Ghent University Hospital. Methods Patients with melanoma (stage III-IV), who received at least one cycle of ICI as adjuvant treatment between 2018 and 2021 were included in this retrospective cohort study. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Other outcomes of interest were relapse patterns and safety. Results 59 patients were included, with a median follow-up of 36 months. Disease recurrence or death of any cause was observed in 25/59 (42.4%) of the patients. The median RFS was 56.0 months (95%CI 36.1–75.9 months). At 48 months, RFS and OS were 55.9% and 84%, respectively. 9/23 (39%) recurrences were locoregional and 14/23 (60.9%) patients developed distant metastasis as first recurrence, including 2 (3.4%) with brain metastasis. Median time to recurrence was 9 months (range 2–56 months). 35/59 (59.3%) completed one year of adjuvant treatment, 12/59 (20.3%) stopped because of recurrence and 10/59 (16.9% because of toxicity. Immune-related adverse events wereseen in 29/59 (49.4%) patients, 10/59 (16.9%) developed grade 3-4 toxicity. Conclusion This study confirms the real-world efficacy and safety of adjuvant ICI for melanoma, achieving RFS and OS comparableto the pivotal clinical trials. About 40% of patients develop arelapse, mainly during the adjuvant treatment. The outcomes ofpatients progressing during adjuvant ICI are poor, emphasizing the need of prospective and real-world studies on optimal management after progression on (neo)adjuvant treatment.

Single-Cell Analysis Identifies Distinct Populations of Cytotoxic CD4+ T Cells Linked to the Therapeutic Efficacy of Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma.

The involvement of cytotoxic CD4+ T cells (CD4+ CTLs) and their potential role in dictating the response to immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC) remains an unexplored area of research. Utilizing single-cell RNA sequencing, we analyzed the immunophenotype and expression patterns of CD4+ T lymphocyte subtypes in mRCC patients, followed by preliminary validation via multi-immunofluorescent staining. In addition, we obtained a comprehensive immunotherapy dataset encompassing single-cell RNA sequencing datasets and bulk RNA-seq cohorts from the European Genome-Phenome Archive and ArrayExpress database. Utilizing the CIBERSORTx deconvolution algorithms, we derived a signature score for CD4+ CTLs from the bulk-RNA-seq datasets of the CheckMate 009/025 clinical trials. Single-cell analysis of CD4+ T lymphocytes in mRCC reveals several cancer-specific states, including diverse phenotypes of regulatory T cells. Remarkably, we observe that CD4+ CTLs cells constitute a substantial proportion of all CD4+ T lymphocyte sub-clusters in mRCC patients, highlighting their potential significance in the disease. Furthermore, within mRCC patients, we identify two distinct cytotoxic states of CD4+ T cells: CD4+GZMK+ T cells, which exhibit a weaker cytotoxic potential, and CD4+GZMB+ T cells, which demonstrate robust cytotoxic activity. Both regulatory T cells and CD4+ CTLs originate from proliferating CD4+ T cells within mRCC tissues. Intriguingly, our trajectory analysis indicates that the weakly cytotoxic CD4+GZMK+ T cells differentiate from their more cytotoxic CD4+GZMB+ counterparts. In comparing patients with lower CD4+ CTLs levels to those with higher CD4+ CTLs abundance in the CheckMate 009 and 25 immunotherapy cohorts, the latter group exhibited significantly improved OS and PFS probability. Our study underscores the pivotal role that intratumoral CD4+ CTLs may play in bolstering anti-tumor immunity, suggesting their potential as a promising biomarker for predicting response to ICIs in patients with mRCC.

Faecalibacterium prausnitzii strain EXL01 boosts efficacy of immune checkpoint inhibitors

ABSTRACT Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types. Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine. F. prausnitzii strain EXL01 will be evaluated as an adjuvant to ICI in multiple cancers in the near future.

What prognostic factors have impacted the efficacy of immune checkpoint inhibitors in patients with recurrent or metastatic oral cancer?

BackgroundImmune checkpoint inhibitors (ICIs) are widely adapted for recurrent or metastatic head and neck cancer (RM-HNC), and various studies on its prognostic factors have been reported. We aimed to elucidate the prognostic factors of ICI treatment for RM oral cancer (RM-OC) in a retrospective study. MethodsWe retrospectively reviewed patients with RM-OC treated with ICIs (nivolumab and pembrolizumab) at our department from May 2017 to February 2023. The objective response rate (ORR) for ICI treatment and the relationship between several potential prognostic factors, progression-free survival (PFS), and overall survival (OS) were analyzed statistically. ResultsThe investigation enrolled 31 patients, 16 with nivolumab and 15 with pembrolizumab. There were no significant differences in the ORR or disease control rate between the nivolumab and pembrolizumab groups (p = 0.4578 and 0.2524). In multivariate analysis, the prognostic nutritional index (PNI) and C-reactive protein to albumin ratio (CAR) exhibited statistical correlations with PFS, whereas the use of antibiotics and proton pump inhibitors (PPIs), neutrophil to lymphocyte ratio (NLR), and PNI demonstrated statistical associations with OS. ConclusionOur findings imply that the use of antibiotics and PPIs, which can modify the gut microbiota, may also serve as a prognostic determinant for ICI treatment in RM-OC, consistent with previous studies. Additionally, PNI may be essential in affecting the survival rates of both PFS and OS and could be an exceedingly valuable inflammatory biomarker for RM-OC.

Guanylate binding protein 5 is an immune-related biomarker of oral squamous cell carcinoma: A retrospective prognostic study with bioinformatic analysis.

Cancer utilizes immunosuppressive mechanisms to create a tumor microenvironment favorable for its progression. The purpose of this study is to histologically characterize the immunological properties of the tumor microenvironment of oral squamous cell carcinoma (OSCC) and identify key molecules involved in the immunological microenvironment and patient prognosis. First, overlapping differentially expressed genes (DEGs) were screened from OSCC transcriptome data in public databases. Correlation analysis of DEGs with known immune-related genes identified genes involved in the immune microenvironment of OSCC. Next, stromal patterns of tumor were classified and immunohistochemical staining was performed for immune cell markers (CD3, CD4, Foxp3, CD8, CD20, CD68, and CD163), programmed death-ligand 1 (PD-L1), and guanylate binding protein 5 (GBP5) in resected specimens obtained from 110 patients with OSCC who underwent resection. Correlations between each factor and their prognostic impact were analyzed. Among the novel OSCC-specific immune-related genes screened (including ADAMDEC1, CXCL9, CXCL13, DPT, GBP5, IDO1, and PLA2G7), GBP5 was selected as the target gene. Histopathologic analysis showed that multiple T-cell subsets and CD20-positive cells were less common in the advanced stages, whereas CD163-positive cells were more common in advanced stages. The immature type in the stromal pattern category was associated with less immune cell infiltration, lower expression of PD-L1 in immune cells, lower expression of GBP5 in the stroma, and shorter overall survival and recurrence-free survival. Expression of GBP5 in the tumor and stroma correlated with immune cell infiltration of tumors and PD-L1 expression in tumor and immune cells. Patients with low tumor GBP5 expression and high stromal expression had significantly longer overall survival and recurrence-free survival. The stromal pattern category may reflect both invasive and immunomodulatory potentials of cancer-associated fibroblasts in OSCC. GBP5 has been suggested as a potential biomarker to predict the prognosis and therapeutic efficacy of immune checkpoint inhibitors.

The Role of Immunotherapy in the Treatment of Gynecologic Cancers: A Systematic Review.

Gynecologic cancers remain a significant health burden worldwide. Immunotherapy has emerged as a promising treatment approach across various cancer types. To evaluate the efficacy and safety of immune checkpoint inhibitors, alone or in combination with other therapies, in the treatment of gynecologic cancers. We searched PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, and ClinicalTrials.gov for clinical trials of immunotherapy in gynecologic cancers. Randomized controlled trials and prospective studies were included. MMAT tool was used to assess the quality of the studies. Risk of bias was assessed using appropriate tools for each study design. Seventeen studies met inclusion criteria, encompassing ovarian, endometrial, and cervical cancers. Immune checkpoint inhibitors, particularly in combination with standard therapies, demonstrated improved progression-free survival across multiple trials. Notable results include improved outcomes with pembrolizumab in endometrial and cervical cancers, and promising combinations of PARP inhibitors with checkpoint inhibitors in ovarian cancer. Safety profiles were generally consistent with known effects of immunotherapy. Immunotherapy shows significant promise in improving outcomes for patients with gynecologic cancers. Further research is needed to optimize patient selection and combination strategies.

Anti-PD-(L)1-Based Neoadjuvant Therapy in Head and Neck Carcinoma: a Meta-analysis of Prospective Clinical Trials.

This meta-analysis aims to evaluate the efficacy and safety of antiprogressive disease (PD)-(L)1-based neoadjuvant therapy in head and neck squamous cell carcinoma (HNSCC) patients and identify potential prognostic biomarkers. Databases were systematically searched for prospective clinical trials evaluating the efficacy and safety of anti-PD-(L)1-based neoadjuvant therapy for HNSCC before January 12, 2024. We estimated the efficacy and safety of neoadjuvant immune checkpoint inhibitors. Subgroup and sensitivity analyses were further performed. A total of 570 patients from 20 studies were included. The pooled major pathological response (MPR), pathological complete response (pCR), and partial pathological response (PPR) rates were 30.7%, 15.3%, and 68.2%, respectively. Surgical complications, surgical delayed rate, all grade treatment-related adverse effects (TRAEs) and ≥Grade 3 TRAEs were 0.6%, 0.3%, 82.6%, and 9.7%, respectively. Best MPR or pCR rate was detected in patients receiving neoadjuvant anti-PD-(L)1 therapy + radiotherapy (with MPR rate of 75.5% and pCR rate of 51.1%) and neoadjuvant anti-PD-(L)1 therapy + chemotherapy groups (with MPR rate of 57.5% and pCR rate of 26.7%). No differences were detected in subgroups stratified by neoadjuvant treatment cycles, human papillomavirus (HPV) status, and tumor location. Patients with baseline Combined Positive Score (CPS) ≥ 20 have higher MPR and pCR rates compared to patients with CPS < 20. High Tumor Cell Proportion Score was also associated with MPR and pCR. Objective response rate is a strong predictor of MPR (odds ratio [OR] = 7.78, 95% confidence interval [CI] = 3.20%-18.91%) and pCR (OR = 3.24, 95% CI = 1.40%-7.48%). Anti-PD-(L)1-based neoadjuvant therapy was effective and safe for HNSCC patients.

Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis.

There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, P < .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, P < .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, P = .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, P = 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, P < .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, P < .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, P < .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, P < .05). ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.

The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Fecal, duodenal, and tumor microbiota composition of esophageal carcinoma patients, a longitudinal prospective cohort.

The microbiome has been associated with chemotherapy and immune checkpoint inhibitor efficacy. How this pertains to resectable esophageal carcinoma is unknown. Our aim was to identify microbial signatures in resectable esophageal carcinoma associated with response to neoadjuvant chemoradiotherapy with or without an immune checkpoint inhibitor. From 2 prospectively collected esophageal carcinoma cohorts (n = 172 in total) treated with neoadjuvant chemoradiotherapy alone (n = 132) or a combination of neoadjuvant chemoradiotherapy and an immune checkpoint inhibitor (n = 40), fecal samples were available at baseline, during treatment, and presurgery. Additionally, in the immune checkpoint inhibitor-treated patients, tumor and duodenal snap frozen biopsies were collected over time. Fecal, tumor, and duodenal DNA were extracted for 16S ribosomal RNA sequencing. Associations were investigated between microbiome composition pathological complete response and progression-free survival (PFS). There was a statistically significant shift in the microbiota profile of the fecal, tumor, and duodenal microbiota over time. In the total cohort, patients with a pathological complete response had a stable fecal alpha diversity, while the diversity of poor responders decreased during treatment (P = .036). Presurgery, lower alpha diversity (<4.12) was related to worse PFS (log-rank P = .025). Baseline tumor biopsies of patients with short PFS had more Fusobacterium. A low baseline duodenal alpha diversity (<3.96) was associated with worse PFS (log-rank P = .012). Lower intestinal alpha diversity was associated with worse response and survival of esophageal carcinoma patients. In tumor biopsies, Fusobacterium was more abundant in patients with poor PFS. After further mechanistic validation, these findings may aid in response prediction and the design of novel microbiome modulating treatments for esophageal carcinoma patients.

Thoracic lymphangitis as an immune-related adverse event: a case report

The efficacy of immune checkpoint inhibitors (ICIs) has been widely recognized in several cancers and is now being used in the perioperative setting for lung cancer.We recently encountered an immune-related adverse event that has not been previously reported: thoracic lymphangitis, which occurred after postoperative ICI treatment for lung cancer. The patient complained of breathlessness and her condition rapidly progressed to hypoxia grade 3. Chest computed tomography revealed significant lymphostasis. With high-dose steroid treatment, the patient showed improvement.Therefore, as the frequency of neoadjuvant, adjuvant, and perioperative ICI use is expected to increase, it is crucial to understand and monitor this adverse event.

A novel signature constructed by mitochondrial function and cell death-related gene for the prediction of prognosis in bladder cancer

Bladder urothelial carcinoma (BLCA) presents a persistent challenge in clinical management. Despite recent advancements demonstrating the BLCA efficacy of immune checkpoint inhibitors (ICI) in BLCA patients, there remains a critical need to identify and expand the subset of individuals who benefit from this treatment. Mitochondria, as pivotal regulators of various cell death pathways in eukaryotic cells, exert significant influence over tumor cell fate and survival. In this study, our objective was to investigate biomarkers centered around mitochondrial function and cell death mechanisms to facilitate prognostic prediction and guide therapeutic decision-making in BLCA. Utilizing ssGSEA and LASSO regression, we developed a prognostic signature termed mitochondrial function and cell death (mtPCD). Subsequently, we evaluated the associations between mtPCD score and diverse clinical outcomes, including prognosis, functional pathway enrichment, immune cell infiltration, immunotherapy response analysis and drug sensitivity, within high- and low-risk subgroups. Additionally, we employed single-cell level functional assays, RT-qPCR, and immunohistochemistry to validate the differential expression of genes comprising the mtPCD signature. The mtPCD signature comprises a panel of 10 highly influential genes, strongly correlated with survival outcomes in BLCA patients and exhibiting robust predictive capabilities. Importantly, individuals classified as high-risk according to mtPCD score displayed a subdued overall immune response, characterized by diminished immunotherapeutic efficacy. In summary, our findings highlight the development of a novel prognostic signature, which not only holds promise as a biomarker for BLCA prognosis but also offers insights into the immune landscape of BLCA. This paradigm may pave the way for personalized treatment strategies in BLCA management.

Adjuvant treatment with anti-PD-1 in acral melanoma: A nationwide study.

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM.

Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies.

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Inhibition of DNMTs increases neoantigen-reactive T-cell toxicity against microsatellite-stable colorectal cancer in combination with radiotherapy

The therapeutic efficacy of immunotherapy is limited in the majority of colorectal cancer patients due to the low mutational and neoantigen burdens in this immunogenically “cold” microsatellite stability-colorectal cancer (MSS-CRC) cohort. Here, we showed that DNA methyltransferase (DNMT) inhibition upregulated neoantigen-bearing gene expression in MSS-CRC, resulting in increased neoantigen presentation by MHC class I in tumor cells and leading to increased neoantigen-specific T-cell activation in combination with radiotherapy. The cytotoxicity of neoantigen-reactive T cells (NRTs) to DNMTi-treated cancer cells was highly cytotoxic, and these cells secreted high IFNγ levels targeting MSS-CRC cells after ex vivo expansion of NRTs with DNMTi-treated tumor antigens. Moreover, the therapeutic efficacy of NRTs further increased when NRTs were combined with radiotherapy in vivo. Administration of DNMTi-augmented NRTs and radiotherapy achieved an ∼50 % complete response and extended survival time in an immunocompetent MSS-CRC animal model. Moreover, remarkably, splenocytes from these mice exhibited neoantigen-specific T-cell responses, indicating that radiotherapy in combination with DNMTi-augmented NRTs prolonged and increased neoantigen-specific T-cell toxicity in MSS-CRC patients. In addition, these DNMTi-augmented NRTs markedly increase the therapeutic efficacy of cancer vaccines and immune checkpoint inhibitors (ICIs). These data suggest that a combination of radiotherapy and epi-immunotherapeutic agents improves the function of ex vivo-expanded neoantigen-reactive T cells and increases the tumor-specific cytotoxic effector population to enhance therapeutic efficacy in MSS-CRC.

A comprehensive supportive care program for fine-tuning cancer immunotherapy.

Supportive care has become a new pilar of modern oncology, and a great deal of research is being conducted in that area, especially on immune checkpoint inhibitors (ICIs), to help fine-tune immunotherapy. Four major areas of supportive care can enhance responsiveness to cancer immunotherapy whilst minimizing adverse effects: diet (indirectly, by modulating the microbiota or directly, by modulating the immune system), physical activity (by modulating the immune system), electronic patient-reported outcomes (ePRO) (by detecting and treating immune-related adverse events early on), and co-medication management (to possibly suppress those drugs that negatively affect the efficacy of ICIs). Therefore, patients treated with ICIs could receive a systematic multimodal supportive care program encompassing regular nutritional counseling, regular physical activity under the supervision of a physical activity professional, ePRO follow-up, and regular pharmaceutical counseling. This type of approach needs to be evaluated in well-conducted randomized clinical trials.