Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy.

BACKGROUND: The mechanism of tumor immune escape and progression in colorectal cancer (CRC) is widely investigated in-vitro to help understand and identify agents that might play a crucial role in response to treatment and improve the overall survival of CRC patients. Several mechanisms of immune escape and tumor progression, including expression of stemness markers, inactivation of immunoregulatory genes by methylation, and epigenetic silencing, have been reported in CRC, indicating the potential of demethylating agents as anti-cancer drugs. Of these, a chemotherapeutic demethylating agent, Decitabine (DAC), has been reported to induce a dual effect on both DNA demethylation and histone changes leading to an increased expression of target biomarkers, thus making it an attractive anti-tumorigenic drug. METHODS: We compared the effect of DAC in primary 1076 Col and metastatic 1872 Col cell lines isolated and generated from patients' tumor tissues. Both cell lines were treated with DAC, and the expression of the NY-ESO-1 cancer-testis antigen, the PD-L1 immunoinhibitory marker, and the CD44, Nanog, KLF-4, CD133, MSI-1 stemness markers were analyzed using different molecular and immunological assays. RESULTS: DAC treatment significantly upregulated stemness markers in both primary 1076 Col and meta-static 1872 Col cell lines, although a lower effect occurred on the latter: CD44 (7.85 fold; ***p = 0.0001 vs. (4.19 fold; *p = 0.0120), Nanog (4.1 fold; ***p < 0.0001 vs.1.69 fold; ***p = 0.0008), KLF-4 (4.33 fold; ***p < 0.0001 vs.2.48 fold; ***p = 0.0005), CD133 (16.77 fold; ***p = 0.0003 vs.6.36 fold; *p = 0.0166), and MSI-1 (2.33 fold; ***p = 0.0003 vs.2.3 fold; ***p = 0.0004), respectively. Interestingly, in the metastatic 1872 Col cells treated with DAC, the expression of both PD-L1 and NY-ESO-1 was increased tenfold (*p = 0.0128) and fivefold (***p < 0.0001), respectively. CONCLUSIONS: We conclude that the upregulation of both stemness and immune checkpoint markers by DAC treatment on CRC cells might represent a mechanism of immune evasion. In addition, induction of NY-ESO-1 may represent an immuno-therapeutic option in metastatic CRC patients. Finally, the combination of DAC and anti-PD-1/anti-PD-L1 antibodies treatment should represent a potential therapeutic intervention for this group of patients.

The complex network of transcription factors, immune checkpoint inhibitors and stemness features in colorectal cancer: A recent update.

Cancer immunity is regulated by several mechanisms that include co-stimulatory and/or co-inhibitory molecules known as immune checkpoints expressed by the immune cells. In colorectal cancer (CRC), CTLA-4, LAG3, TIM-3 and PD-1 are the major co-inhibitory checkpoints involved in tumor development and progression. On the other hand, the deregulation of transcription factors and cancer stem cells activity plays a major role in the development of drug resistance and in the spread of metastatic disease in CRC. In this review, we describe how the modulation of such transcription factors affects the response of CRC to therapies. We also focus on the role of cancer stem cells in tumor metastasis and chemoresistance and discuss both preclinical and clinical approaches for targeting stem cells to prevent their tumorigenic effect. Finally, we provide an update on the clinical applications of immune checkpoint inhibitors in CRC and discuss the regulatory effects of transcription factors on the expression of the immune inhibitory checkpoints with specific focus on the PD-1 and PD-L1 molecules.

Successful rechallenge with cisplatin following cisplatin induced ischemic cerebrovascular accident in a patient with small cell lung cancer.

Cisplatin is a widely used platinum-based chemotherapy agent. Its common adverse effects are neuropathy, nephrotoxicity, electrolyte abnormality, and rarely causing thrombotic vascular toxicity. We present a patient known to have small-cell lung cancer who developed ischemic cerebrovascular accident (CVA) after receiving chemotherapy regimen including cisplatin.

COVID-19 Vaccination in Cancer Patients: A Review Article.

Coronavirus disease 2019 (COVID-19) infection is caused by severe acute respiratory syndrome coronavirus 2. Adults with cancer are immunocompromised due to several causes including cancer itself and immunosuppressive therapy. Thus, cancer patients are more susceptible to develop COVID-19 infection. As COVID-19 vaccines became available, patients with cancer would benefit from receiving the vaccine. This article aims to review the recent evidences and recommendations about COVID-19 vaccination in cancer patients.Current guidelines recommend that patients with cancer should have the priority to receive the vaccine given their immunocompromised state. The timing of administration varies depending on cancer type and treatment. Generally, the vaccine should be given before starting the chemotherapy if possible or in between chemotherapy cycles and away from nadir phase. For other cancer treatments, it is recommended to give the vaccine when there is evidence of blood count recovery. In general, induction therapy and treatment for newly diagnosed patients should not be delayed for the vaccination purpose. It is noteworthy to mention that cancer patients especially those with hematologic malignancies might have absented or attenuated response to the vaccine due to their pathophysiological status.On the other hand, the current vaccine guidelines have been criticized for lacking evidence on some important topics that need to be addressed. Firstly, some vaccines have been granted an emergency use authorization, prior to the usual comprehensive safety and efficacy evaluation process. Secondly, specific populations including cancer patients were excluded from the approval trials for safety reasons. Finally, some recommendations regarding the COVID-19 vaccines are extrapolated from other vaccines studies. Further studies are required to fill these gaps and observational studies that include cancer patients are warranted to have a better understanding of the safety and efficacy of the vaccines in cancer patients.

A primary squamous cell carcinoma of the sigmoid colon in a young patient: A case report and literature review.

Colon cancer is among the most common types of cancer with adenocarcinomas being the most common type. Herein we report a young patient who presented with primary colonic squamous cell carcinoma without risk factors. To the best of our knowledge, this is the youngest patient with such diagnosis worldwide.

Histopathologic Predictors of Survival and Recurrence in Resected Ampullary Adenocarcinoma: International Multicenter Cohort Study.

OBJECTIVE: The aim of the study was to define histopathologic characteristics that independently predict overall survival (OS) and disease-free survival (DFS), in patients who underwent resection of an ampullary adenocarcinoma with curative intent. SUMMARY BACKGROUND DATA: A broad range of survival rates have been described for adenocarcinoma of the ampulla of Vater, presumably due to morphological heterogeneity which is a result of the different epitheliums ampullary adenocarcinoma can arise from (intestinal or pancreaticobiliary). Large series with homogenous patient selection are scarce. METHODS: A retrospective multicenter cohort analysis of patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma in 9 European tertiary referral centers between February 2006 and December 2017 was performed. Collected data included demographics, histopathologic details, survival, and recurrence. OS and DFS analyses were performed using Kaplan-Meier curves and Cox proportional hazard models. RESULTS: Overall, 887 patients were included, with a mean age of 66 ±â€Š10 years. The median OS was 64 months with 1-, 3-, 5-, and 10-year OS rates of 89%, 63%, 52%, and 37%, respectively. Histopathologic subtype, differentiation grade, lymphovascular invasion, perineural invasion, T-stage, N-stage, resection margin, and adjuvant chemotherapy were correlated with OS and DFS. N-stage (HR = 3.30 [2.09-5.21]), perineural invasion (HR = 1.50 [1.01-2.23]), and adjuvant chemotherapy (HR = 0.69 [0.48-0.97]) were independent predictors of OS in multivariable analysis, whereas DFS was only adversely predicted by N-stage (HR = 2.65 [1.65-4.27]). CONCLUSIONS: Independent predictors of OS in resected ampullary cancer were N-stage, perineural invasion, and adjuvant chemotherapy. N-stage was the only predictor of DFS. These findings improve predicting survival and recurrence after resection of ampullary adenocarcinoma.

In vitro effect of IL-2 in combination with pazopanib or sunitinib on lymphocytes function and apoptosis of RCC cells.

OBJECTIVE: Combination of immunotherapy with tyrosine kinase inhibitors (TKIs) has been used with some success for the treatment of metastatic renal cell carcinoma. Herein we evaluate the in vitro effect of high-dose interleukin-2 (HDIL-2) and pazopanib or sunitinib on the lymphocyte function and on induction of apoptosis in renal cell carcinoma (RCC) cell lines. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors or RCC patients were treated with different HDIL-2/TKI combinations. Effects of different combinations on proliferation and cytotoxic activity of PBMCs were evaluated, in addition to their effect on apoptosis of three different RCC cell lines. RESULTS: While sunitinib did not inhibit the proliferation of various immune cells induced by HDIL-2, pazopanib appeared to inhibit the HDIL-2-induced proliferation of these cells. Interestingly, none of the HDIL-2/TKI combinations appeared to compromise the functional properties of these cells. Additionally, significant proportion of RCC cell lines treated with pazopanib alone underwent apoptosis, while the proportions of apoptotic cells post-HDIL-2 or sunitinib were not different from the background. Furthermore, the combination of HDIL-2/pazopanib did not inhibit the pazopanib-induced RCC apoptosis. CONCLUSION: The combination of HDIL-2 with either pazopanib or sunitinib exerts different anticancer mechanisms that could enhance the treatment efficacy.

A case of fatal cetuximab-induced interstitial lung disease during the first weeks of treatment.

Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor. It has demonstrated activity against a number of cancers including lung, head and neck, and colorectal. The most common side effects associated with this agent are dermatological; however, other types of toxicities have been reported with varying frequencies. Here, we report a case of interstitial lung disease that developed within the first 4 weeks of cetuximab treatment initiation in a patient with metastatic colorectal cancer and led to patient death. Early fatal pulmonary events secondary to cetuximab is rarely reported in the literature; this case report highlights the importance of awareness among treating health care professionals of this potentially fatal toxicity.

Eribulin for advanced breast cancer: a drug evaluation.

Eribulin is a synthetic microtubule dynamics inhibitor that was developed from a marine natural product halichondrin B. It exhibited in vitro and in vivo activities against a wide number of malignancies. A number of advanced phase trials showed improved survival following eribulin treatment in pretreated advanced breast cancer patients. This review provides an overview of the background to the therapeutic use of eribulin in oncology, including its pharmacology, pharmacokinetics, clinical efficacy, safety, and potential economic factors.

High-dose interleukin-2 can produce a high rate of response and durable remissions in appropriately selected patients with metastatic renal cancer.

Metastatic renal cancer remains hard to treat and the treatment is generally palliative. However, high-dose interleukin-2 (HD IL-2) produced 5% to 10% complete remissions and most of these were durable. With the advent of newer treatments with less toxicity, the role of HD IL-2 is uncertain. We present here a case series of 72 patients with metastatic renal cancer given first-line treatment with HD IL-2. From 2003 to 2006, the patients were offered treatment with HD IL-2 irrespective of their histologic features (retrospective cohort). From 2006 to 2008, the treatment was only offered to patients after stratification into risk groups based on histologic criteria (prospective cohort). In the early series, the response rate to HD IL-2 was 27% (8/30), but with prospective stratification of patients by histology the response rate was 52% (21/40) in the group with favorable histologic features. Combining outcome for all patients with the favorable histology (including those identified retrospectively) 49% (28/57) responded with 25% (14/57) achieving a complete remission and these seem durable. Patients with metastatic renal cancer should be carefully assessed for their suitability to undergo treatment with first-line systemic therapy with HD IL-2 as in carefully selected patients it has a high-rate response and durable remissions.

Management of a new isolated metastasis during sunitinib treatment in renal cell carcinoma patients: a lesson from two cases.

Metastatic renal cell carcinoma (mRCC) is a difficult to treat malignancy and currently Sunitinib is a standard of care first-line therapy. A new metastasis during the treatment is considered a sign of drug failure and alternative therapeutic methods should be tried. Here, we report 2 cases of newly diagnosed isolated metastasis during Sunitinib treatment of mRCC patients. Our management plan included local palliative therapy to the lesion followed by recommencing of Sunitinib. This resulted in a good symptomatic relief locally as well as good overall control of the disease.

T cell-based immunotherapy of metastatic renal cell carcinoma: modest success and future perspective.

Metastatic renal cell carcinoma (MRCC) remains a challenging malignancy to treat. Cancer immunotherapies have been extensively explored in melanoma and RCC as they poorly respond to conventional cytotoxic agents but show responses to a variety of immunologic agents. The recent considerable success of T cell-based immunotherapy in melanoma warrants further efforts to apply this treatment to other cancers including MRCC. Although RCC is an immunosensitive cancer, similar attempts in MRCC have shown a very limited success. In this review, we summarize the clinical data on T cell-based immunotherapies for MRCC showing the modest success that has been achieved to date. More importantly, we discuss potential strategies for improving its efficacy for the treatment of MRCC in light of the important achievements for treating metastatic melanoma. In particular, the growing evidence of success by combining expanded tumor-infiltrating lymphocytes with lymphodepletion merits investigation in MRCC. Identifying new RCC-associated antigens, optimized methods, and conditions for detection, isolation, and/or modification and expansion of tumor-specific T cells are all important strategies to be pursued for improving T cell-based immunotherapy of MRCC.

Vaccination of patients with metastatic renal cancer with modified vaccinia Ankara encoding the tumor antigen 5T4 (TroVax) given alongside interferon-alpha.

Approximately 90% of renal cell tumors overexpress the tumor antigen 5T4. The attenuated strain of vaccinia virus, modified vaccinia Ankara, has been engineered to express 5T4 (TroVax). We conducted an open-label phase 1/2 trial in which TroVax was administered alongside interferon-alpha (IFNalpha) to 11 patients with metastatic renal cell carcinoma. Antigen-specific cellular and humoral responses were monitored throughout the study, and clinical responses were assessed by measuring the changes in tumor burden by computed tomography scan (Response Evaluation Criteria In Solid Tumors). The primary objective was to assess the safety, immunogenicity, and efficacy of TroVax when given alongside IFNalpha. Treatment with TroVax plus IFNalpha was well tolerated with no serious adverse events attributed to TroVax. All 11 patients mounted 5T4-specific antibody responses and 5 (45%) mounted cellular responses. No objective tumor responses were seen, but the overall median time to progression (TTP) of 9 months (range: 2.1 to 26+ mo) was longer than expected for IFNalpha alone. For the 10 clear cell patients the TTP ranged from 3.9 to 26+ months, with a median TTP of 10.4 months. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared with that expected for IFNalpha alone is encouraging and warrants further investigation.

Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma.

PURPOSE: CD4(+)CD25(+) regulatory T (T(reg)) cells are present in increased numbers in patients with advanced cancer and CD25(+) T cell depletion potentiates tumour immunity in animal models. The aim of this study was to assess the feasibility and safety of adoptive transfer of CD25(+) depleted autologous T cells in patients with advanced renal cell carcinoma and to examine resulting changes in lymphocyte subsets. PATIENTS AND METHODS: Six patients with advanced renal cell carcinoma underwent leukapheresis followed by conditioning chemotherapy with cyclophosphamide and fludarabine. The autologous leukapheresis product was depleted of CD25(+) cells using CliniMACS System then re-infused into the patient. RESULTS: Efficient CD25(+) depletion from all leukapheresis products was achieved and 0.55-5.87 x 10(7)/kg CD3(+) cells were re-infused. Chemotherapy related haematological toxicity was observed, but blood counts recovered in all patients allowing discharge after a mean inpatient stay of 21 days. One patient subsequently developed a rapidly progressive neurological syndrome. A transient reduction in CD25(+) subset was noted in the peripheral blood of 5 out of 6 patients with evidence of increased T cell responses to PHA in 4 out of 6 patients. One patient showed increased specific proliferative responses to the tumour associated antigen h5T4 coinciding with the nadir of T(reg) cells. CONCLUSIONS: Given the transient nature of the reduction in CD25(+) subset and the observed toxicity there is a need to explore further strategies to improve the safety and efficacy of this approach. Nevertheless, the results provide proof of concept in potentiation of tumour antigen T cell responses when T(reg) cell levels are depleted.