Treatment Of Advanced-stage Cancer Research Articles

Comprehensive evaluation of biopolymer immune implants for peritoneal metastasis carcinoma therapy.

Immunotherapy has been widely used in the treatment of advanced stage cancers with spreading metastases, while the fully activation of immune system often requires sustained and long-acting immune stimulation by immunotherapeutic agents. In previous studies, we designed a biopolymer immune implant by dynamic covalent bonds and achieved sustained release of loaded immunotherapeutic agents, thus stimulated systemic immune activation and elicited immune memory effects. Herein, we further optimized the implants and carried out a comprehensive evaluation of the implants on peritoneal metastasis carcinoma (PMC) therapy. Our results showed that the implants fabricated with 8-arm polyethylene glycol amine (8-arm PEG-NH2) and 40% oxidation degree dextran (ODEX) exhibited a satisfactory degradation time for activating the antitumor immunity. The drug combination of oxaliplatin (OxP) and resiquimod (R848) could be sustainably released from the implants for 18days. The implants cured 75% of mice with PMC and elicited immune memory effects to resist tumor re-challenge without obvious side effects observed. Mechanism analysis revealed that the implants could serve as an in-situ vaccine to enhance the infiltration of activated dendritic cells (DCs), T cells and natural killer (NK) cells inside the tumor, as well as increase the serum tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin 12 (IL-12) levels. These results strongly support the clinical translation potential of this sustained released biopolymer immune implants for PMC therapy.

Pharmacophore-based virtual screening approaches to identify novel molecular candidates against EGFR through comprehensive computational approaches and in-vitro studies.

Alterations to the EGFR (epidermal growth factor receptor) gene, which primarily occur in the axon 18-21 position, have been linked to a variety of cancers, including ovarian, breast, colon, and lung cancer. The use of TK inhibitors (gefitinib, erlotinib, lapatinib, and afatinib) and monoclonal antibodies (cetuximab, panitumumab, and matuzumab) in the treatment of advanced-stage cancer is very common. These drugs are becoming less effective in EGFR targeted cancer treatment and developing resistance to cancer cell eradication, which sometimes necessitates stopping treatment due to the side effects. One in silico study has been conducted to identify EGFR antagonists using other compounds, databases without providing the toxicity profile, comparative analyses, or morphological cell death pattern. The goal of our study was to identify potential lead compounds, and we identified seven compounds based on the docking score and four compounds that were chosen for our study, utilizing toxicity analysis. Molecular docking, virtual screening, dynamic simulation, and in-vitro screening indicated that these compounds' effects were superior to those of already marketed medication (gefitinib). The four compounds obtained, ZINC96937394, ZINC14611940, ZINC103239230, and ZINC96933670, demonstrated improved binding affinity (-9.9kcal/mol, -9.6kcal/mol, -9.5kcal/mol, and -9.2kcal/mol, respectively), interaction stability, and a lower toxicity profile. In silico toxicity analysis showed that our compounds have a lower toxicity profile and a higher LD50 value. At the same time, a selected compound, i.e., ZINC103239230, was revealed to attach to a particular active site and bind more tightly to the protein, as well as show better in-vitro results when compared to our selected gefitinib medication. MTT assay, gene expression analysis (BAX, BCL-2, and β-catenin), apoptosis analysis, TEM, cell cycle assay, ELISA, and cell migration assays were conducted to perform the cell death analysis of lung cancer and breast cancer, compared to the marketed product. The MTT assay exhibited 80% cell death for 75µM and 100µM; however, flow cytometry analysis with the IC50 value demonstrated that the selected compound induced higher apoptosis in MCF-7 (30.8%) than in A549.

A unique vaccine for birth control and treatment of advanced stage cancers secreting ectopically human chorionic gonadotropin

This article is a tribute and homage to Gerard Chaouat who invited me to contribute this article. My years in France have remained very memorable to me. Reviewed briefly is the vaccine that was made against human chorionic gonadotropin (hCG) to prevent unwanted pregnancy in sexually active women. It has now been developed as a genetically engineered recombinant vaccine and passed onto industry for its production under good manufacturing practices (GMP) conditions for confirmatory trials. The trials have received the approval of the Drugs Controller General of India. The trials have started but have been interrupted by the coronavirus disease 2019 (COVID-19) pandemic. This vaccine is likely to have another highly beneficial application in the treatment of cancers expressing ectopically hCG.

CD47: the next checkpoint target for cancer immunotherapy.

Cancer immunotherapy using checkpoint blockade has brought about a paradigm shift in the treatment of advanced-stage cancers. Unfortunately, not all patients benefit from these therapies, paving the way for other immune checkpoints to be targeted. CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. Recently, CD47 blockade by Hu5F9-G4 has shown promise combined with Rituximab in non-Hodgkin's lymphoma. Here we review the complex structure and various physiological functions of CD47 and their implications in cancer biology. Further, this review considers future directions and challenges in advancing this promising target platform to widespread therapeutic use.

Abstract 254: Predictors of Immune Checkpoint Inhibitor Associated Cardiotoxicity

Background: Immune checkpoint inhibitors (ICIs), including programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitors, are increasingly used in treatment of advanced stage cancers due to a well-established mortality benefit. ICI therapy is associated with immune mediated toxicity which may impact any organ system. Cardiovascular toxicities are rare based on existing data, but associated with high mortality rates. Objectives: The aim of this study is to determine whether preexisting cardiac conditions and/or cardiac therapies are associated with an increased or decreased risk of developing cardiotoxicity after ICI exposure. Methods: All patients treated with ICI therapy from March 2011 through October 2019 at our institution were identified. Demographic information, treatment dates, pre-treatment cardiac conditions and comorbidities, cancer types, pre-treatment cardiac biomarkers, and pre-treatment cardio-protective medication use were determined for each patient. New cardiac diagnoses after ICI exposure were identified in the medical record. Multivariate logistic regression was used determine the association between preexisting cardiac conditions and/or cardiac therapies and the development of cardiotoxicity after ICI exposure. Results: There were 902 patients identified with 1071 ICI exposures. The majority of exposures were to a PD-1 inhibitor (70%), with the most common drugs being pembrolizumab (42.8%) and nivolumab (26.5%). Eighty-nine new cardiac diagnoses were coded after initiation of ICI therapy. Sixteen events occurred within 30 days of initial exposure to an ICI and likely represent new cases of immune checkpoint inhibitor associated cardiotoxicity (incidence 1.5%). Of these events, one was confirmed as myocarditis, seven were heart failure without confirmation of myocarditis, three were arrhythmia, one was pericarditis, three were myocardial infarction and one was ventricular tachyarrhythmia/sudden cardiac death, without confirmed myocarditis or heart failure. There was an additional case of myocarditis identified within 90 days of initial exposure to ICI therapy, and a third case identified 115 days following exposure. All three patients who developed myocarditis died, consistent with the known high mortality rate of ICI associated myocarditis. One of the patients who developed myocarditis received pembrolizumab, one nivolumab and one cemiplimab (all PD-1 inhibitors). A history of heart failure increased the odds of developing a cardiac toxicity by 2.3 fold (95% CI 1.4 to 3.3, p<0.001) and prior beta-blocker exposure decreased the odds by 1.8 fold (95% -2.9 to -0.7, p=0.002). Conclusion: A history of heart failure is associated with an increased odds of developing cardiotoxicity after ICI exposure while prior beta blocker exposure appears to be protective.

Repurposing drugs as pro-oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers.

Over the last decade, three major advances have contributed in improving the response rates against cancer including, immunotherapy; greater understanding of the molecular, biochemical, and cellular mechanisms in carcinogenesis thereby providing drug targets; and identification of reliable biomarkers for early detection to facilitate the earlier stage treatment of disease. However, no single universal cancer cure has yet been found, although combinations from the above areas have steadily improved survival outcomes. Hence, chemotherapy remains a key component in the oncologist's arsenal for cancer therapy, despite frequent development of drug resistance and more aggressive cancers with onset of advanced stage metastases. The focus here is to explore the repurposing of old drugs that cause pro-oxidative overload to overcome onset of resistance to chemotherapy and enhance chemotherapeutic responses, particularly against metastatic cancer. Excellent examples of US Food and Drug Administration approved drugs suitable for repurposing are the potent and specific thioreductase inhibitor auranofin and the nonsteroidal anti-inflammatory drug, celecoxib. Recently, both drugs were shown to selectively target and kill metastatic cancer cells and cancer stem cells (CSCs), predominantly by promoting excessive mitochondrial reactive oxygen species. Thus, targeting intracellular redox systems of advanced stage metastatic cancer cells and CSCs can promote an overload of pro-oxidative stress to activate the intrinsic pathway for programmed cell death. It is envisaged that more clinical studies will incorporate longer term use of repurposed drugs, such as auranofin or celecoxib, to target redox systems in cancer cells as part of common practice postcancer diagnosis, providing enhanced chemotherapeutic responses and increased cancer survival.

Abstract 5929: microRNA control of an oHSV vector allows for robust oncolysis and selective control of viral replication in normal tissues

Abstract Effective treatment of advanced stage cancer with oncolytic viruses requires potent cancer cell-specific oncolytic activity. We modified oncolytic HSV (oHSV) to utilize a novel conditional-lethal strategy that retains all viral genes to maintain potency of the oncolytic virus, yet block replication in normal cells. In addition, we armed the virus with extracellular matrix decreasing enzyme to promote viral spread and immunomodulatory payloads to increase recruitment and effector function of immune cells. To enhance the selectivity of viral replication to tumor cells, Oncorus engineered oHSVs containing microRNA (miRNA)-binding cassettes (miR-T) in essential genes required for viral replication. The first Oncorus clinical candidate, ONCR-1, under development for the treatment recurrent glioblastoma multiform (GBM), has been attenuated for replication in neurons, the most trophic cell type for HSV. Neuronal attenuation was achieved by inserting binding sites for a highly specific neuronal miRNA, miR-124, into the 3′UTR of the essential ICP4 gene. We demonstrate that these engineered miR-124 response elements can selectively inhibit the expression of ICP4 and VP5 as well as the expression of ONCR-1 payloads. This attenuation strategy eliminates viral replication in miR-124 expressing cells without compromising oncolytic activity in cancer cells, thereby providing a therapeutic window. We extended the design oHSV attenuation by profiling of miRNAs expression in panels of solid tumors and non-diseased tissue counterparts in other potentially high-risk tissues, prioritized to indications amenable to local or systemic administration. We leveraged our comprehensive normal and malignant tissue dataset to identify numerous highly expressed unique non-cancerous tissue-specific candidate miRNAs. Insertion of miR-T cassettes into HSV-1 genes collaborated to stall the early steps in the viral replication cycle and further increased the depth and breadth of oHSV attenuation in non-disease tissue relative to the single miR-T cassette in ICP4. We found that miR-122, a highly expressed miRNA in normal hepatocytes, is low or absent in many carcinoma cells. Insertion of miR-122 cassette into the 3′UTR of an immediate early gene, ICP27, inhibited completely viral replication in miR-122 expressing cells. oHSV with dual miR-124 and miR-122 was potently attenuated cells expressing one or both miRs while displaying a robust oncolytic activity in malignant cells. We have shown that insertion of miR-T cassettes in essential viral genes effectively attenuates oHSV replication in normal human cells, and most importantly, robust oncolysis was retained in cancer cells. This work extends the miR-T paradigm to multiple viral genes with diverse miRNA targets, thus expanding the protection of normal tissues and facilitating the application of oHSV to the treatment of multiple malignancies. Citation Format: Edward M. Kennedy, Terry Farkaly, Caitlin Goshert, Allison Colthart, Prajna Behera, Peter Grzesik, Kyle Grant, Michael Paglia, Paola Grandi, Christophe Quéva, Mitchell Finer, Lorena Lerner. microRNA control of an oHSV vector allows for robust oncolysis and selective control of viral replication in normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5929.

Monitoring immune-checkpoint blockade: response evaluation and biomarker development.

Cancer immunotherapy using immune-checkpoint blockade (ICB) has created a paradigm shift in the treatment of advanced-stage cancers. The promising antitumour activity of monoclonal antibodies targeting the immune-checkpoint proteins CTLA-4, PD-1, and PD-L1 led to regulatory approvals of these agents for the treatment of a variety of malignancies. Patients might experience clinical benefits from treatment with these agents, despite unconventional patterns of tumour response that can be misinterpreted as disease progression, warranting a new, specific approach to evaluate responses to immunotherapy. In addition, biomarkers that can predict responsiveness to ICB are being extensively investigated to further advance precision immunotherapy. Herein, we review the biological mechanisms underlying the unconventional response patterns associated with ICB, describe strategies for the objective assessments of such responses, and also highlight the ongoing efforts to identify biomarkers, in order to guide treatment with ICB. We provide state-of-the-art knowledge of immune-related response evaluations, identify unmet needs requiring further investigations, and propose future directions to maximize the benefits of ICB therapy.

Immunological Approaches for Treatment of Advanced Stage Cancers Invariably Refractory to Drugs

Worldwide, deaths due to cancers are taking an increasing toll. Invariably over time cancer cells become refractory to available drugs. At this stage, the tumor is largely metastasized and not amenable to radical surgery or focal radiations. This review seeks to bring out the existence of heterogeneity of cell types in each cancer, and proposes adoption of a combined approach employing more than one therapeutic agent for a more lasting treatment. Also proposed is the use of monoclonal therapeutic antibodies and vaccines against ectopically expressed key molecules for killing of cancer cells and prevention of their multiplication. Focus is on androgenindependent carcinoma of prostate and a variety of cancers expressing ectopically human chorionic gonadotropin (hCG) and/or Carcino-embryonic antigen (CEA). The utility of using antibodies directed against cell membrane located epitopes for homing and delivery of a safe anti-cancerous compound Curcumin to cancer cells is also described.

A unique vaccine for control of fertility and therapy of advanced‐stage terminal cancers ectopically expressing human chorionic gonadotropin

Human chorionic gonadotropin (hCG) appears soon after fertilization of the egg and plays a critical role in implantation of the embryo leading to the beginning of pregnancy. Vaccines developed against hCG prevent pregnancy without impairment of ovulation and disturbance of menstrual regularity. A new recombinant vaccine hCGβ-LTB has been developed that is highly immunogenic in various strains of mice and intended for the control of fertility in women. An additional use of this vaccine is likely to be treatment of advanced-stage cancers that ectopically express hCG.

Taking care of the patient with cancer: How treatment practices vary by the experience of the treating oncologist.

e19665 Background: Oncologists have multiple choices in managing their patients. With biologic agents unique toxicites are being seen. These agents require new basic science knowledge and diagnostic skills. As oncologists age and get further away from their academic training, just how comfortable are they in caring for patients and how clinically competent are they? Are oncologists taking care of the entire patient or are they just giving drugs to treat their patient’s disease? Methods: 37 of the 50 invited community oncologists participated in this study. There were 40 questions with 10 patient vignettes dealing with various medical and psychosocial issues involved in the treatment of advanced stage cancer. An analysis was done between oncologists in practice less than 10 years (15), from 10 to 20 (8) and over 20 (14). Results: The younger physicians better understood the mode of action of the newer agents. All respondents felt comfortable using them even as the newer toxicities required care from other specialties. Attendence at ASCO was not a high priority for any group.The older oncologists thought that ASCO attendence had become “irrelevant” due to a host of reasons. All respondents felt that CME courses “on-line” and local and regional meetings gave them the information that they needed to care for their patients. Their understanding of statistical end points in clinical trials was equally poor. All groups used consultants for cardiopulmonary issues while the older physicians were more comfortable handling the septic neutropenic patient. The younger physicians were uncomfortable and less knowledgeable in dealing with psychosocial issues. They relied quite heavily on others while the experienced physicians handled these issues with little difficulty or stress. Conclusions: The more experienced oncologist were more comfortable dealing with palliative and end of life issues. They also used subspecialty colleagues less often by doing more “general internist” work. Attendence at the ASCO annual meeting is of much less importance as many of the respondents felt that “cost-benefit” strongly favored not attending but going to a post-ASCO review course and other locoregional events.

Combination of apigenin treatment with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects

BackgroundIt is important to develop innovative therapies for advanced stage cancers in addition to the conventional therapies including chemotherapy, radiation and surgery. Antigen-specific immunotherapy has emerged as a novel alternate therapy for advanced stage cancers, which may be employed in conjunction with conventional therapies.MethodsIn the current study, we tested the effect of treatment with the chemotherapeutic agent, apigenin in combination with DNA vaccines encoding the HPV-16 E7 antigen linked to heat shock protein 70 (HSP70) in the control of the E7-expressing tumor, TC-1.ResultsWe observed that treatment with apigenin rendered the TC-1 tumor cells more susceptible to lysis by E7-specific cytotoxic CD8+ T cells. Furthermore, treatment of TC-1 tumor cells with apigenin was found to enhance apoptotic tumor cell death in vitro in a dose-dependant manner. We showed that TC-1 tumor-bearing mice treated with apigenin combined with E7-HSP70 DNA generate highest frequency of primary and memory E7-specific CD8+ T cells, leading to potent therapeutic anti-tumor effects against E7-expressing tumors.ConclusionThus, apigenin represents a promising chemotherapeutic agent, which may be used in combination with immunotherapy for the treatment of advanced stage cancers. The clinical implications of the current strategy are discussed.

DENDRITIC CELL BASED VACCINES: PROGRESS IN IMMUNOTHERAPY STUDIES FOR PROSTATE CANCER

No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. The literature was reviewed for major contributions to a growing number of studies that demonstrate the potential of DC based immunotherapeutics for prostate cancer. Background topics relating to DC based immunotherapy theory and practice are also addressed. DCs have been recognized as the most efficient antigen presenting cells that have the capacity to initiate naive T cell response in vitro and in vivo. During their differentiation and maturation pathways, dendritic cells can efficiently capture, process and present antigens for T cell activation. These characteristics make DC an attractive choice as the cellular adjuvant for cancer vaccines. Advances in DC generation, loading, and maturation methodologies have made it possible to generate clinical grade vaccines for various human trials. More than 100 DC vaccine trials, including 7 studies of patients with advanced prostate cancer have been reported to date. These vaccines were generally well tolerated with no significant adverse toxicity reported. Clinical responders have been identified in these studies. The new prospects opened by DC based vaccines for prostate cancer are fascinating. When compared to conventional treatments, DC vaccinations have few side effects. Improvements in patient selection, vaccine delivery strategies, immune monitoring and vaccine manufacturing will be crucial in moving DC based prostate cancer vaccines closer to the clinics.

Use of cisplatin, 5-fluorouracil, and second-look laparotomy for the management of gastrointestinal adenocarcinoma in three dogs

Three dogs with advanced-stage adenocarcinoma of the gastrointestinal tract were treated by use of resection, adjuvant chemotherapy with cisplatin and 5-fluorouracil, and second-look laparotomy (SLL). In combination with histologic examination of biopsy specimens obtained during the procedure, SLL is the most accurate diagnostic procedure for identification of residual or recurrent microscopic or macroscopic abdominal neoplasia; however, to the authors' knowledge, there are no reports of its clinical use in the field of veterinary oncology. This lack of clinical use in animals is likely because of factors such as cost, procedure-associated risks perceived by the owners and veterinarians, lack of data to define proper clinical application, and, perhaps to some degree, an entrenched belief that treatment of advanced stage cancer in animals is inappropriate. Nevertheless, the use of SLL should be considered for evaluation of abdominal tumors or intra-abdominal metastases in dogs that appear to be in complete clinical remission near or at the anticipated completion of chemotherapy (especially if effective second-line chemotherapy protocols are available) or when secondary cytoreduction might be beneficial.

Combination of gamma-irradiation and dendritic cell administration induces a potent antitumor response in tumor-bearing mice: approach to treatment of advanced stage cancer.

We investigated a new approach to the treatment of advanced stage cancer, a combination of apoptosis-inducing therapy and dendritic cell (DC) administration. MethA sarcoma and C3 tumor containing defined tumor-specific antigens in form of peptides' epitopes were selected as experimental mouse models. Sites of established subcutaneous tumors were gamma-irradiated with 10 Gy 3-5 times with 4-5 day interval. DCs generated from bone marrow of syngeneic mice were injected i.v. and s.c. after each irradiation. A large number of cell tracker-labeled DCs accumulated at the site of the irradiated tumor after s.c. injections. This effect was not observed in non-irradiated tumors. Almost all of these DCs bound GFP-labeled MethA cells in tumor tissue. Interferon-gamma production by splenocytes in response to the tumor-specific MHC class I matched peptides was determined by ELISPOT assays. The combination of gamma-irradiation and DC administration, but not each of the treatments alone resulted in a significant increase in T cell response to the specific, but not to the control peptides. An increased proportion of tumor peptide-specific CD8(+)-cells was found only in that group of mice using staining with tetramers. DCs with defective presentation of antigen via MHC class I or MHC class II pathways were unable to induce peptide-specific T cell response. The combination of gamma-irradiation and DC administration but not each of the treatments alone resulted in a dramatic antitumor effect. A substantial proportion of mice completely rejected their tumors (80% in case of MethA sarcoma and 40% in case of C3 tumor). In the rest of the mice, tumor growth was notably suppressed or completely blocked. These data suggest that the combination of apoptosis-inducing therapy and DC administration may be an attractive approach to the treatment of advanced cancer.

Lawrence E. Scheving, Ph.D.: Chronobiology pioneer, “Full Bird” colonel, and native son

Lawrence E. Scheving, Ph.D.: Chronobiology pioneer, “Full Bird” colonel, and native son