The Role of m6A Epigenetic Modification in the Treatment of Colorectal Cancer Immune Checkpoint Inhibitors

Tumor immunotherapy, one of the efficient therapies in cancers, has been called to the scientific community’s increasing attention lately. Among them, immune checkpoint inhibitors, providing entirely new modalities to treat cancer by leveraging the patient’s immune system. They are first-line treatments for varieties of advanced malignancy, such as melanoma, gastrointestinal tumor, esophageal cancer. Although immune checkpoint inhibitors (ICIs) treatment has been successful in different cancers, drug resistance and relapses are common, such as in colorectal cancer. Therefore, it is necessary to improve the efficacy of immune checkpoint therapy for cancer patients who do not respond or lowly response to current treatments. N6-methyladenosine (m6A), as a critical regulator of transcript expression, is the most frequently internal modification of mRNA in the human body. Recently, it has been proposed that m6A epigenetic modification is a potential driver of tumor drug resistance. In this report, we will briefly outline the relevant mechanisms, general treatment status of immune checkpoint inhibitors in colorectal cancer, how m6A epigenetic modifications regulate the response of ICIs in CRC and provide new strategies for overcoming the resistance of ICIs in CRC.

Role of Microenvironment in Ovarian Tumourisation

Background. Metastasis is a formidable complication of malignant neoplasms, with therapy not always effective in advanced malignancy. Metastasis is a multistep process involving the cancer cell detachment from primary tumour, intravasation, extravasation and invasion into the target organ. Early metastasis stages are well understood, whilst the impact of tumour microenvironment on the disease progression and advancement remains a matter of debate.Aim. An immunohistochemical study of the adaptive and reactive properties of greater omentum with metastatic involvement in ovarian cancer.Materials and methods. We examined greater omentum tissue samples from 40 patients with verifi ed stage 3a and b ovarian cancers. For light microscopy, samples were fi xed in 10 % formalin, dehydrated, paraffi n-embedded and stained with Mayer’s haematoxylin and eosin. Immunohistochemical assays used monoclonal antibodies against CD7, CD4, CD8, CD 68, VEGF, D2-40 and CD44 proteins. Statistical data analysis was performed with Statistica v. 7.0 soft ware.Results and discussion. Analyses of the greater omentum tissues revealed cases of leucocyte-bank encapsulation of metastatic foci. Higher CD7+ and CD8+ cell counts were observed in encapsulation, possibly influencing the greater omentum reactive and adaptive properties. Higher CD44-expressing cell counts were also detected in greater omentum samples lacking encapsulation. Angiogenesis marker-expressing cells (e.g., VEGF and CD34) predominated in greater omentum tissues lacking leucocyte-bank encapsulation of metastatic foci.Conclusion. Events in tumour microenvironment may be indicative of a preserved or reduced organ adaptivity, the latter facilitating disease progression.

Abstract 11514: Extracorporeal Membrane Oxygenation is a Feasible Life Saving Modality for Adult Patients With Neoplasms- Outcomes and Trends in the Last Two Decades

Introduction: Extracorporeal Membrane Oxygenation (ECMO) is utilized in the management of severe respiratory and circulatory failure. Advanced malignancy is a relative contraindication but the indication for ECMO in the oncologic population has not been clearly established due to the wide spectrum of malignant disease and prognoses. Hypothesis: ECMO is a feasible treatment modality in selected adult oncologic population. Method: The Extracorporeal Life Support Organization (ELSO) database was queried for patients older than 18 years with an International Classification of Diseases (ICD) code of neoplasm over the past two decades (2000-2019). The data were divided into two decades to analyze and compare the trends with background and outcomes. Results: One thousand, six hundred, and ninety-seven patients met inclusion criteria from the last decade which is more than 15 times the number from the previous decade (n=110). Compared with the previous decade, ECMO was used more in patients with older age (56 vs 50.5 years old; p<0.001), cardiac and extracorporeal cardiopulmonary resuscitation (ECPR) support type (p = 0.001), higher P/F ratio (79.0 vs 61.8; p=0.001), and lower oxygenation index (23.0 vs 35.6; p< 0.001) in the last decade. Although survival did not show significant improvement overall (38.9% [660 of 1697] vs 33.6% [37 of 110]; p=0.272), survival in pulmonary ECMO has significantly improved in the last decade (41.6% [409 of 983] vs 29.1% [23 of 79]; p=0.030). Diagnosis of hematologic malignancy, ECPR, and hematopoietic stem cell transplant were identified as predictors of poor prognosis (p = 0.025, <0.001, and 0.021 respectively). Conclusion: Utilization of ECMO for patients with neoplasms has increased over time mirroring the overall increase of adult ECMO. With careful patient selection, ECMO can be successful in oncologic population.

812 Erythema nodosum-like toxicity in an immunotherapy treated patient is accompanied by oligoclonal memory activated CD4 T cells

BackgroundImmune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can be associated with immune related adverse events (irAE). Here we present a case report of a rare dermatologic toxicity occurring in a melanoma patient with isolated brain metastasis. After surgical resection, the patient was treated with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) combination therapy followed by single agent nivolumab with ongoing, excellent response. During nivolumab, the patient developed an erythema nodosum (EN)-like irAE. The condition resolved after potassium iodine treatment and nivolumab therapy was resumed. To understand the pathogenesis of this irAE, we examined samples from this patient's blood, brain metastasis and tissue biopsy of the EN toxicity.MethodsRNA and T cell receptor (TCR) sequencing on the patient's brain metastasis and site of irAE were performed. We also performed RNA sequencing on 3 non-ICI EN patients. RNA in situ hybridization (RNAish) for CD4, CD8 and granzyme B, and the most abundant TCR identified was conducted on the patient's site of toxicity. Single cell RNA/TCR sequencing was carried out on the patient's peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution.ResultsRNAish showed that the most abundant TCR (20% of total TCR sequencing reads at the site of toxicity) colocalized with CD4 at the site of toxicity. According to CIBERSORT deconvolution, the site of toxicity had high memory activated CD4 T cells and low M2 macrophage infiltration, which is different from the brain metastasis and non-ICI-induced EN cases. Compared to non-ICI EN, the EN skin biopsy was also enriched for interferon response and inflammation related genes. In the peripheral blood, cytotoxic CD8 T cells clonally expanded during EN toxicity, accompanied by a decrease in naïve/memory CD4 T cells. The TCR repertoire in the site of toxicity did not overlap with that in the tumor or PBMC.ConclusionsWe found oligoclonal memory activated CD4 T cells are enriched at the site of toxicity, suggesting their association with EN toxicity. The unique TCR repertoire, gene expression profile and immune cell composition at the site of toxicity could indicate that the EN toxicity is distinct from the anti-tumor immunity and analogous non-ICI autoimmunity. Future work will focus on determining the antigen for this irAE and determining its relevancy to other skin toxicities and EN autoimmune conditions.Ethics ApprovalIRB 100178 and 161485ConsentApproval under IRB 100178

477 COM902 (Anti-TIGIT antibody) monotherapy – preliminary evaluation of safety, tolerability, pharmacokinetics and receptor occupancy in patients with advanced solid tumors (NCT04354246)

BackgroundCOM902 is an IgG4 fully human high-affinity monoclonal antibody, inhibitor of TIGIT (T cell Ig and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain) binding to poliovirus receptor (PVR). TIGIT blockade by COM902 was shown to enhance anti-tumor immunity in pre-clinical models. We hypothesized that COM902 as monotherapy will have an acceptable safety and tolerability profile in subjects with advanced solid tumors.MethodsUtilizing an accelerated titration and 3+3 study design we enrolled 18 patients (pts) at the following COM902 doses 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 mg/kg IV Q3 wks. Key primary objectives were to evaluate the safety, tolerability (CTCAE v5.0), to characterize the pharmacokinetics (PK) and to select a recommended dose for expansion (RDFE). An exploratory objective was evaluation of peripheral receptor occupancy (RO). Key inclusion criteria: Age ≥18 yrs, histologically/cytologically confirmed advanced malignancy who have exhausted all available standard therapy or not a candidate for standard therapy. Patients with performance status ECOG 0-1, prior ICI permissible. Dose-limiting toxicities (DLTs) were evaluated within a 21-day window in the 1st cycle of dose escalation.ResultsIn the safety population [N=18], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥2pts] were fatigue 7 pts (39%) all G1/2, diarrhea 3 pts (17%) all G1/2. Two pts reported DLTs deemed related to study drug, a pt with G2 nausea (single pt cohort, 0.01 mg/kg) and a pt with G3 atrial fibrillation (1 mg/kg). Serious adverse events were reported in 2 pts, 1 pt with atrial fibrillation (deemed by the investigator as possibly related to COM902) and 1 pt with spinal cord compression (deemed by the investigator as unrelated to COM902, related to disease). Preliminary PK profiles were generally dose proportional and peripheral RO above 90% was reported from 0.1 mg/kg dose.ConclusionsCOM902 has an acceptable safety, tolerability and PK profiles. A COM902 3 mg/kg IV Q3 wks is the RDFE. Enrollment into combination cohort (COM902 + COM701), for evaluation of safety/tolerability at the RDFE of both study drugs, combination dose expansion (COM902 + COM701) in pts with HNSCC, NSCLC and CRC-MSS and COM902 monotherapy dose expansion (pts with multiple myeloma) all at the RDFE of study drug(s) are planned. Data cut June 28, 2021.Trial RegistrationNCT04354246Ethics ApprovalThe study obtained approval from IRBs of the participating clinical trial sites. The study participants gave informed consent before taking part.o 0002: MOD01006350 (START)o 0003: 20202320 (West Cancer Center)o 0012: 2020–0195 (MDACC)o 0013: MOD01006350 (START midwest)o 0014: 20202320 (OSU)

The mechanosensitive TRPV2 calcium channel controls melanoma invasiveness and metastatic potential.

Discovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes remain often unclear. Here, we showed that the expression of the plasma membrane TRPV2 calcium channel is a prominent feature in melanoma progression and dissemination. In fact, TRPV2 activity was sufficient to confer an invasive phenotype to non-invasive melanoma cells. Conversely, the invasive and migratory potential of highly metastatic melanoma cells was abolished upon TRPV2 silencing. Mechanistically, TRPV2 supports melanoma cells aggressiveness by being a new regulator of the calpain-dependent maturation of focal adhesion, and actin cytoskeleton remodeling. Finally, TRPV2 overexpression is a marker of advanced malignancy and bad prognosis in human melanoma tumor samples. Altogether, TRPV2-induced Ca2+ signaling orchestrates in vitro motility and invasiveness of melanoma cells, as well as in vivo metastatic melanoma tumors dissemination.

Neutrophils Extracellular Traps Inhibition Improves PD-1 Blockade Immunotherapy in Colorectal Cancer

Immune checkpoint inhibitors can improve the prognosis of patients with advanced malignancy; however, only a small subset of advanced colorectal cancer patients in microsatellite-instability-high or mismatch-repair-deficient colorectal cancer can benefit from immunotherapy. Unfortunately, the mechanism behind this ineffectiveness is unclear. The tumor microenvironment plays a critical role in cancer immunity, and may contribute to the inhibition of immune checkpoint inhibitors and other novel immunotherapies in patients with advanced cancer. Herein, we demonstrate that the DNase I enzyme plays a pivotal role in the degradation of NETs, significantly dampening the resistance to anti-PD-1 blockade in a mouse colorectal cancer model by attenuating tumor growth. Remarkably, DNase I decreases tumor-associated neutrophils and the formation of MC38 tumor cell-induced neutrophil extracellular trap formation in vivo. Mechanistically, the inhibition of neutrophil extracellular traps with DNase I results in the reversal of anti-PD-1 blockade resistance through increasing CD8+ T cell infiltration and cytotoxicity. These findings signify a novel approach to targeting the tumor microenvironment using DNase I alone or in combination with immune checkpoint inhibitors.

Surgical Diseases Management during COVID-19 Crisis at a Tertiary Care Hospital of India: Our Institutional Strategy

Introduction In response to the national coronavirus disease 2019 (COVID-19) pandemic, all hospitals and medical institutes gave priority to COVID-19 screening and to the management of patients who required hospitalization for COVID-19 infection. Surgical departments postponed all elective operative procedures and provided only essential surgical care to patients who presented with acute surgical conditions or suspected malignancy. Ample literature has emerged during this pandemic regarding the guidelines for safe surgical care. We report our experience during the lockdown period including the surgical procedures performed, the perioperative care provided, and the specific precautions implemented in response to the COVID-19 crisis. Materials and Methods We extracted patient clinical data from the medical records of all surgical patients admitted to our tertiary care hospital between the March 24th, 2020 and May 31st, 2020. Data collected included: patient demographics, surgical diagnoses, surgical procedures, nonoperative management, and patient outcomes. Results Seventy-seven patients were included in this report: 23 patients were managed medically, 28 patients underwent a radiologic intervention, and 23 patients required an operative procedure. In total eight of the 77 patients died due to ongoing sepsis, multiorgan failure, or advanced malignancy. Conclusion During the COVID-19 lockdown period, our surgical team performed many lifesaving surgical procedures and appropriately selected cancer operations. We implemented and standardized essential perioperative measures to reduce the spread of COVID-19 infection. When the lockdown measures were phased out a large number of patients remained in need of delayed elective and semi-elective operative treatment. Hospitals, medical institutes, and surgical leadership must adjust their priorities, foster stewardship of limited surgical care resources, and rapidly implement effective strategies to assure perioperative safety for both patients and operating room staff during periods of crisis.

Pharmacologic and Non-Pharmacologic Dyspnea Management in Advanced Cancer Patients

As there is a high propensity for patients with advanced malignancy to experience refractory dyspnea, it is necessary for physicians to be well-versed in the management of these patients’ dyspneic symptoms. For symptomatic treatment of cancer patients with dyspnea, both pharmacologic and non-pharmacologic methods should be considered. The main source of pharmacologic symptom management for dyspnea is oral and parenteral opioids; benzodiazepines and corticosteroids may serve as helpful adjuncts alongside opioid treatments. However, oxygen administration and nebulized loop diuretics have not been shown to clinically benefit dyspneic cancer patients. Applying non-pharmacologic dyspnea management methods may be valuable palliative therapies for advanced cancer patients, as they provide benefit with negligible harm to the patient. Advantageous and minimally harmful non-pharmacologic dyspnea therapies include facial airflow, acupuncture and/or acupressure, breathing exercises, cognitive behavioral therapy, music therapy, and spiritual interventions. Thus, it is vital that physicians are prepared to provide symptomatic care for dyspnea in advanced cancer patients as to minimize suffering in this patient population during definitive cancer treatments or hospice care.