Immunological Checkpoint Inhibitors Research Articles

Promises of Protein Kinase Inhibitors in Recalcitrant Small-Cell Lung Cancer: Recent Scenario and Future Possibilities.

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.

Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer.

Tumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs). To reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1. Intratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only. These data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses.

REVIEWING ADVANCES IN UNDERSTANDING AND TARGETING THE MAPK SIGNALING PATHWAY IN HEPATOCELLULAR CARCINOMA PROGRESSION AND THERAPEUTICS

Hepatocellular carcinoma (HCC) is a severe and increasingly prevalent health issue affecting individuals globally. Recent research endeavors in the clinical domains have lately focused more on the MAPK signaling pathway in HCC. Activating mutations in the RAS and RAF genes, which greatly activate the MAPK pathway in malignancies, are rare in HCC patients, yet over 50% of them have activated the pathway. This suggests that other factors may be responsible for the activation of the signaling pathway in HCC. MAPK signaling is important to carcinogenesis, and it is often altered in human cancers. The drug resistance in targeted therapy against RTKs in HCC may arise from mutations in downstream components (RAS, RAF, MEK, ERK), resistant mutations within RTKs, and additional alternative pathways like PI3K and YAP may also develop the resistance. Epigenetic processes and chromatin remodeling are crucial to pharmacological tolerance to MAPK regulation. This review will focus on the latest developments in our knowledge of the cellular and molecular processes to activate the MAPK signaling pathway, as well as possible treatment approaches that specifically target this pathway in relation to HCC. The study also investigates the clinical efficacy of molecular-targeted treatments, including tyrosine kinase inhibitors and immunological checkpoint inhibitors and highlights the use of combination therapy for HCC.

Exocrine pancreatic insufficiency secondary to checkpoint inhibitors. A clinical case report

Modern immunotherapy has been a flood of hope for both, patients diagnosed with cancer and for oncologists, but this has forced health professionals, within their different disciplines, to internalize and educate themselves regarding new diagnostic challenges of immunological-related adverse events (irEA), difficult to address and even more so to treat in direct proportion to their frequency of appearance. Although gastrointestinal toxicity due to immunological checkpoint inhibitors (ICI) is well known, its leading role is at the expense of enterocolitis and hepatitis, among others, relegating less than 1% to cases such as pancreatitis, where morphological and histopathological alterations , both of the ducts and of the pancreatic parenchyma, can compromise endocrine and/or exocrine function. The latter, reported in the literature only in a few cases, has a complex and difficult diagnostic approach with a flowery and disabling symptomatic sign picture, which motivates the present bibliographic review. The case of a female patient diagnosed with metastatic melanoma under treatment with nivolumab with development of exocrine pancreatic insufficiency (EPI) 7 months after suspending immunotherapy is discussed below.

Evaluation of a self-questionnaire to screen for neurological complications associated with immunological checkpoint inhibitors: Are we missing something?

IntroductionImmunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Neurological complications seem to have a profile quite distinct from that of toxicities related to chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed. Objectives(i) To evaluate the value of a self-questionnaire in screening for neurological ICI-related complications. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset might occur. MethodPatients followed in dermatology department for skin cancers treated with ICI, completed every infusion a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the questionnaire's data. ResultsIn total, 149 patients completed≥1 questionnaire, with a median delay of 174 days from the start of treatment. A total of 229 questionnaires were completed between July 2019 and December 2019. 38 patients were identified for a neurological consultation. None of these patients had a neurological event attributable to ICI. During the follow-up, only one patient had a neurological event related to ICI, which was not revealed by the questionnaire. DiscussionNeurological signs in ICI-treated-skin-cancer context are more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These results highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists.

Programmed death ligand 1 (PD-L1) expression in gastric cancer: literature review

Gastric cancer is one of the most common oncological diseases at the present time, so research in this area is very significant and relevant. Immunological checkpoint inhibitors have previously demonstrated their effectiveness and safety in various solid tumors, however, with regard to stomach cancer, to date, ambiguous results have been presented. Tumor cells express programmed death ligand 1 (PD-L1), which binds to its programmed death receptor 1 (PD-1). Immune defense plays a key role in the initiation and progression of the disease. Understanding the regulatory mechanism of PD-L1 in gastric cancer can lead to significant progress in immunotherapy, as well as contribute to the adequate selection of patients treated with checkpoint inhibitors. In the review, we conducted an in-depth study of PD-L1 expression and regulatory immunosuppressive mechanisms in gastric cancer and methods for assessing PD-L1 status, and also studied the results of current clinical trials in which inhibitors of immunological control points were considered in combination with and without chemotherapy for this oncopathology.

Potential Applications of Nanoparticles in Improving the Outcome of Lung Cancer Treatment.

Lung cancer is managed using conventional therapies, including chemotherapy, radiation therapy, or a combination of both. Each of these therapies has its own limitations, such as the indiscriminate killing of normal as well as cancer cells, the solubility of the chemotherapeutic drugs, rapid clearance of the drugs from circulation before reaching the tumor site, the resistance of cancer cells to radiation, and over-sensitization of normal cells to radiation. Other treatment modalities include gene therapy, immunological checkpoint inhibitors, drug repurposing, and in situ cryo-immune engineering (ICIE) strategy. Nanotechnology has come to the rescue to overcome many shortfalls of conventional therapies. Some of the nano-formulated chemotherapeutic drugs, as well as nanoparticles and nanostructures with surface modifications, have been used for effective cancer cell killing and radio sensitization, respectively. Nano-enabled drug delivery systems act as cargo to deliver the sensitizer molecules specifically to the tumor cells, thereby enabling the radiation therapy to be more effective. In this review, we have discussed the different conventional chemotherapies and radiation therapies used for inhibiting lung cancer. We have also discussed the improvement in chemotherapy and radiation sensitization using nanoparticles.

Cardiotoxicity surveillance among patients with cancer treated with immunotherapy.

2636 Background: With the advancements of immunotherapy procedures and, more specifically, immunological checkpoint inhibitors (ICIs), the scenario of cancer treatment, whether in its early or advanced stages, have changed. With the expansion of ICIs usage, cardiovascular toxicities have been reported, but more robust data are needed to guide the follow-up of patients and toxicity prevention. Methods: This research is a single-centered, prospective observational cohort study that evaluated patients treated with ICIs regardless of indication, with or without chemotherapy combination. Patients underwent echocardiography evaluation with global longitudinal strain (GLS) and myocardial work, electrocardiogram, and collection of biomarkers before the start of treatment, in the second month after treatment started, and every 3 months, subsequently. Evaluations stopped once treatment completed one year, or the medication was discontinued either due to toxicity or disease progression. Cardiotoxicity (CT) was defined by ≥ 10% reduction in left ventricular ejection fraction (LVEF) by less than 50%, troponin elevation by ≥ 0,30 ng/ml, or reduction in relative GLS by ≥ 15%. Frequencies were compared using Fisher's comparative test, as appropriate, and Mann-Whitney test for numerical variables. Statistical significance will be considered as p < 0.05 for two-tailed tests. Results: Outof the 98 patients scheduled for treatment, 39 patients underwent at least 2 evaluations and had their exams analyzed. There was a 26% incidence of overall CT, with half of these patients by LVEF reduction criteria and, considering only patients with lung cancer, there was an incidence of 35% with CT. Dividing the total sample into CT and non-CT groups, a higher number of men, smokers and patients with lung cancer was observed, as well as a lower LVEF baseline (67% vs 62.50, p = 0.014) in the CT group. Concomitant chemotherapy or higher baseline coronary calcium scores did not appear to increase the risk of CT among patients, but the use of beta-blockers was restricted to patients who did not develop an event. There was a reduction in myocardial work parameters in the 2nd month assessment: global index (GWI) 1833 vs 2334, p = 0.006, constructive work (GCW) 2299 vs 2683, p = 0.040, and work efficiency (GWE) 83 vs 95, p = 0.025 and tendency towards increased myocardial work loss (GWW) 286 vs 116, p = 0.064, in the comparison between groups. Those who met CT criteria had a longer overall survival, as did those who developed other immune-mediated adverse events and metformin users. Conclusions: This was the first study that carried out cardiotoxicity surveillance in patients undergoing immunotherapy, with a surprising finding of events in a small but high-risk sample. The development of immune-mediated toxicities seems to be related with therapeutic response. Also, the use of metformin seems to contribute to this response, as already demonstrated in preclinical studies.

Ocular side effects of modern oncological therapy : Immunological checkpoint and MEK/BRAF signal transduction inhibitors

In recent years, checkpoint inhibitors have revolutionized the treatment of previously untreatable malignant tumors, significantly improving the life expectancy as well as quality of life in many cases. Checkpoint inhibitors comprise agroup of drugs with different mechanisms of action. These include immunological checkpoint inhibitors (iCPI) and intracellular signal transduction inhibitors; however, both substance classes can cause inflammatory or toxic ocular side effects. The frequency of intraocular inflammation (uveitis) is reported to be ca. 1-2%, toxic side effects were observed in up to more than 50% of the patients treated with signal transduction inhibitors. In the following article the main mechanisms of these forms of treatment are characterized. Furthermore, this article presents the currently most frequently used therapeutic agents and their typical ophthalmological side effects to increase awareness and to draw attention to these still rare but increasingly more frequent findings.

Redox Signaling Modulates Activity of Immune Checkpoint Inhibitors in Cancer Patients.

Although immunotherapy is already a staple of cancer care, many patients may not benefit from these cutting-edge treatments. A crucial field of research now focuses on figuring out how to improve treatment efficacy and assess the resistance mechanisms underlying this uneven response. For a good response, immune-based treatments, in particular immune checkpoint inhibitors, rely on a strong infiltration of T cells into the tumour microenvironment. The severe metabolic environment that immune cells must endure can drastically reduce effector activity. These immune dysregulation-related tumour-mediated perturbations include oxidative stress, which can encourage lipid peroxidation, ER stress, and T regulatory cells dysfunction. In this review, we have made an effort to characterize the status of immunological checkpoints, the degree of oxidative stress, and the part that latter plays in determining the therapeutic impact of immunological check point inhibitors in different neoplastic diseases. In the second section of the review, we will make an effort to assess new therapeutic possibilities that, by affecting redox signalling, may modify the effectiveness of immunological treatment.

Evaluation of a self-questionnaire to screen for neurological complications associated with immunological checkpoint inhibitors : are we missing something ? (P4-5.025)

<h3>Objective:</h3> (i) To evaluate the value of a self-questionnaire in screening for neurological complications related to immunological checkpoint inhibitors. (ii) To investigate whether, apart from the subacute complications described in the literature, neurological complications of more insidious onset can occur. <h3>Background:</h3> Immunological checkpoint inhibitors (ICI) have led to a therapeutic revolution in the management of many cancers and indications are increasing. Toxicity of these treatments can be severe dysimmune manifestations. Neurological complications are rare, subacute and seem to have a presentation profile quite distinct from that of toxicities related to anticancer chemotherapy, although it is possible that some manifestations remain under-reported or misdiagnosed. <h3>Design/Methods:</h3> Patients followed in dermatology department for skin cancers and treated with ICI completed every month a neurological screening auto-questionnaire. Patients were selected for a neurological expertise based on the data from the questionnaires. <h3>Results:</h3> 149 patients completed a total of 229 questionnaires between July 2019 and December 2019. Of these, 38 patients were identified for a neurological consultation, and none of the patients consulted had a neurological event per se attributable to ICI. Five patients presented rapid tumoral progression in CNS with neurological impairment. During the follow-up, only one patient had a neurological event related to ICI after 6 months of treatment, and this event was not revealed by the questionnaire completed few weeks before. <h3>Conclusions:</h3> Neurological signs in ICI-treated-skin-cancer context is more often due to tumoral progression. Neurological complications of ICI remain rare and unpredictable. The systematic neurological questionnaire has not been shown to be useful in this context. These result highlight the need to educate patients about possible subacute signs that should lead to contact the treating physicians and the need for a close cooperation between dermatologists/oncologists and neurologists. <b>Disclosure:</b> Dr. Lemarchant has nothing to disclose. Julien Lannoy has nothing to disclose. Sylvain Dubucquoi has nothing to disclose. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for BIogen Idec. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for novartis. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for BMS. Helene Zephir has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion.

Hemophagocytic Lymphohistiocytosis Associated with Immunological Checkpoint Inhibitors: A Pharmacovigilance Study.

Acquired hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition characterized by hyperactivation of macrophages and cytotoxic lymphocytes, combining a series of non-specific clinical symptoms and laboratory disorders. Etiologies are multiple: infectious (mainly viral) but also oncologic, autoimmune or drug-induced. Immune checkpoint inhibitors (ICI) are recent anti-tumor agents associated with a novel profile of adverse events triggered by immune system over-activation. Here, we sought to provide a comprehensive description and analysis of HLH cases reported with ICI since 2014. Disproportionality analyses were performed in order to further explore the association between ICI therapy and HLH. We selected 190 cases, 177 from the World Health Organization pharmacovigilance database and 13 from the literature. Detailed clinical characteristics were retrieved from the literature and from the French pharmacovigilance database. The cases of HLH reported with ICI concerned men in 65% of cases with a median age of 64 years. HLH occurred in an average of 102 days after the initiation of ICI treatment and mostly concerned nivolumab, pembrolizumab and nivolumab/ipilimumab combination. All cases were considered serious. Most cases presented a favorable outcome (58.4%); however, death was reported for 15.3% of patients. Disproportionality analyses showed that HLH was seven times more frequently reported with ICI therapy than with other drugs and three times more than with other antineoplastic agents. Clinicians should be aware of the potential risk of ICI-related HLH to improve the early diagnosis of this rare immune-related adverse event.

Checkpoint inhibitor-induced myocarditis

Immunological checkpoint inhibitors have been revolutionary in the treatment of cancer. A rare but serious adverse effect is the development of heart muscle inflammation (myocarditis). The prevalence of this type of myocarditis is increasing as more cancer patients receive treatment with immune checkpoint inhibitors. Knowledge of immune checkpoint inhibitor-induced myocarditis isimportant to enable early diagnosis and initiation of treatment. In this article we provide a clinical review of this.

FLASH X-ray spares intestinal crypts from pyroptosis initiated by cGAS-STING activation upon radioimmunotherapy

DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8+ T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8+ T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.

CAR-NK Cells for Cancer Therapy: Molecular Redesign of the Innate Antineoplastic Response.

The Chimeric Antigen Receptor (CAR) has arisen as a powerful synthetic biology-based technology with demonstrated versatility for implementation in T and NK cells. Despite CAR T cell successes in clinical trials, several challenges remain to be addressed regarding adverse events and long-term efficacy. NK cells present an attractive alternative with intrinsic advantages over T cells for treating solid and liquid tumors. Early preclinical and clinical trials suggest at least two major advantages: improved safety and an off-the-shelf application in patients due to its HLA independence. Due to the early stages of CAR NK translation to clinical trials, limited data is currently available. By analyzing these results, it seems that CAR NK cells could offer a reduced probability of Cytokine Release Syndrome (CRS) or Graft versus Host Disease (GvHD) in cancer patients, reducing safety concerns. Furthermore, NK cell therapy approaches may be boosted by combining it with immunological checkpoint inhibitors and by implementing genetic circuits to direct CAR-bearing cell behavior. This review provides a description of the CAR technology for modifying NK cells and the translation from preclinical studies to early clinical trials in this new field of immunotherapy.

Abstract 5510: Preclinical study of allogeneic CD19-CAR-DNT cells as an off-the-shelf immunotherapy drug for NHL

Abstract Introduction Allogeneic Double Negative T (DNT, CD3+CD4-CD8-) cells have shown great potential as a novel off-the-shelf immunotherapy drug candidate in clinic trials for r/r/AML patients. This is our first report to demonstrate that CD19-CAR-DNT cells with high percentage of Tscm+Tcm phenotypes have been successfully developed with strong immunotherapeutic effects on Raji-luciferase tumor cells from non-Hodgkin’s lymphoma both in vitro and in vivo. Methods DNT cells were expanded ex vivo from healthy donors and then were transduced with CD19-CAR lentivirus in the presence of IL-2. The CD19-CAR-DNT cell expansions were performed under GMP condition and then harvested and cryo-preserved by CryStor®CS5 in liquid nitrogen for future use. Summary The ex vivo expanded CD19-CAR-DNT cells has more than 50% of Tscm and Tcm phenotypes. The viability and CAR+ percentage of CD19-CAR-DNT cells were 84.40% and 34.98% respectively. The killing of CD19-CAR-DNT cells on Raji-luciferase cells was 77.92% (n=6) at the effector to target ratio of 4:1. Elevated IFN-γ release from CD19-CAR-DNT cells after overnight co-culture with Raji cells was observed. The antitumor efficacy was evaluated in the xenografted NHL mice model. After the first infusion of the cells, the tumor growth inhibitory rates (TGI %) of CD19-CAR-DNT cells at 1×106, 5×106 and 1×107 per mouse on day14 were 80.54%, 98.31% and 99.05% respectively, the killing effects were in a dose-dependent manner. After the second infusion of the CD19-CAR-DNT cells at day 14, median survival times (MST) of the treated three groups mice were elongated till Day60, that is twice longer than that of the xenografted vehicle group. In the subsequent PKPD study, infusion CD19-CAR-DNT cells into Raji-luciferase cell xenografted mice were primarily distributed in lungs, peripheral blood, spleen, and bone marrow within 72h, homing back to liver and spleen on Day36. All animal body weights in both fresh and frozen reconstituted CD19-CAR-DNT cells treated mice were increased with no observed toxicities. Conclusions ex vivo expansion of CD19-CAR-DNT cells were successfully developed to explore its potential as a novel off-the-shelf universal CART drug for malignant B cells leukemia. The cell subsets consist of more than 50% of Tscm and Tcm cells whereas most immunological check point inhibitors were not elevated after priming by target tumor cells except a slight increase of PD-1 molecule. Fresh or frozen CD19-CAR-DNT cells can kill Raji cells in vitro and in vivo studies in a dose-dependent manner although the frozen one showed a delayed killing in vivo. The tumor cells were almost depleted and the MST was significantly increased with NOAEL at 1x107 cells/mouse. The amounts of CD19-CAR-DNT cells are re-distributed from early lungs, peripheral blood to live, spleen later. Citation Format: Liming Yang, Dan Wang, Shangzhi Xu, Liuyang Wang, Jianjun Tong, Honglin Zhu, Man Xu, Xiancai Li, Letu Ji, Chuntao Zheng, Zhiqiang Xiang, Qinghua Sun, Hengcai Wang. Preclinical study of allogeneic CD19-CAR-DNT cells as an off-the-shelf immunotherapy drug for NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5510.

Cooperation in R&amp;D in the pharmaceutical industry: Technological and clinical trial networks in oncology

• Cooperation is essential for the technological and clinical advances of new drugs. • There is more interaction in the development of CTs than patent deposit. • Geographic location is still a relevant factor for cooperation. Organizations cooperate according to their interests in the development of a specific technology. Research and development (R&D) in pharmaceutical industries is essential for the development of new drugs and partnerships are responsible to achieve and maintain competitiveness in the market. Cancer represents a global health problem and new oncology drugs are essential. This study verified how cooperation takes place aimed at the invention (patents) and development (clinical trials - CT) of treatments with the primary target being oncology. Using social network analyses to generate technological discoveries, cooperation networks using patents, and a CT development collaboration network, the 526 CT and 294 patents were analyzed in collaboration between universities, hospitals, companies, and other institutions. The results show the evolution of patents from chemical synthetic processes to biomarkers and immunological checkpoint inhibitors. The associations of the CT network tend to have more partnerships than the patent network, which indicates greater trust and the need for complementary expertise. This study indicates that during the R&D stages of new oncology drugs, organizations search for actors of different types, as experts are needed for each stage. Although companies are predominant in both networks, research institutes play a central role in this connection. This study can be applied for researchers, universities, institutes and companies interested in R&D and in the other therapeutic areas.

Immune Checkpoint Inhibitors in Tumors Harboring Homologous Recombination Deficiency: Challenges in Attaining Efficacy.

Cancer cells harbor genomic instability due to accumulated DNA damage, one of the cancer hallmarks. At least five major DNA Damage Repair (DDR) pathways are recognized to repair DNA damages during different stages of the cell cycle, comprehending base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ). The unprecedented benefits achieved with immunological checkpoint inhibitors (ICIs) in tumors with mismatch repair deficiency (dMMR) have prompted efforts to extend this efficacy to tumors with HR deficiency (HRD), which are greatly sensitive to chemotherapy or PARP inhibitors, and also considered highly immunogenic. However, an in-depth understanding of HRD’s molecular underpinnings has pointed to essential singularities that might impact ICIs sensitivity. Here we address the main molecular aspects of HRD that underlie a differential profile of efficacy and resistance to the treatment with ICIs compared to other DDR deficiencies.

Research Progresses in Immunological Checkpoint Inhibitors for Breast Cancer Immunotherapy.

Tumor immune escape refers to the phenomenon in which tumor cells escape the recognition and attack of the body’s immune system through various mechanisms so that they can survive and proliferate in vivo. The imbalance of immune checkpoint protein expression is the primary mechanism for breast cancer to achieve immune escape. Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)/programmed cell death protein-ligand 1 (PD-L1) are critical immune checkpoints for breast cancer. Immune checkpoint inhibitors block the checkpoint and relieve its inhibition effect on immune cells, reactivate T-cells and destroy cancer cells and restore the body’s ability to resist tumors. At present, immunological checkpoint inhibitors have made significant progress in breast cancer immunotherapy, and it is expected to become a new treatment for breast cancer.

Treatment of BRAF-Mutated Metastatic Melanoma: Immunotherapy or Target Therapy?

Metastatic melanoma has been associated with a poor prognosis, with overall survival rates at 5 years of 10%. Until 2011, the only treatments available for metastatic melanoma were chemotherapy and immunotherapy with interleukin-2. The more in-depth knowledge about the molecular biology of melanoma and the identification of BRAF mutations, which are the most frequently found, allowed us to find new therapeutic targets that came to modify the prognosis of these patients. Currently, the treatments available for metastatic melanoma with BRAF mutation are immunotherapy with immunological checkpoint inhibitors (anti-PD-1 to anti-CTLA-4) and targeted therapy with BRAF inhibitors and MEK inhibitors. However, the first-line therapy to be instituted in these patients remains unknown.