LAG-3 : recent developments in combinational therapies in cancer.

The study of anticancer immune responses and in particular the action of immune checkpoint inhibitors that overcome T cell inhibition has revolutionized metastatic patients' care. Unfortunately, many patients are resistant to these innovative immunotherapies. Over the last decade, several immune checkpoint inhibitors, currently available in the clinic, have been developed, such as anti-PD-1/PD-L1 or anti-CTLA-4. More recently, other immune checkpoints have been characterized, among them lymphocyte activation gene 3 (LAG-3). LAG-3 has been the subject of numerous therapeutic studies and may be involved in cancer-associated immune resistance phenomena. This review summarizes the latest knowledge on LAG-3 as an immunotherapeutic target, particularly in combination with standard or innovative therapies. Indeed, many studies are looking at combining LAG-3 inhibitors with chemotherapeutic, immunotherapeutic, radiotherapeutic treatments, or adoptive cell therapies to potentiate their antitumor effects and/or to overcome patients' resistance. We will particularly focus on the association therapies that are currently in phase III clinical trials and innovative combinations in preclinical phase. These new discoveries highlight the possibility of developing other types of therapeutic combinations currently unavailable in the clinic, which could broaden the therapeutic spectrum of personalized medicine.

Anticancer Tetranuclear Cu(I) Complex Catalyzes a Click Reaction to Synthesize a Chemotherapeutic Agent in situ to Achieve Targeted Dual-Agent Combination Therapy for Cancer.

To develop next-generation metal-based drugs and dual-drug combination therapy for cancer, we proposed to develop a copper (Cu) complex that exerts anticancer function by integrating chemotherapy, immunotherapy and catalyzes a click reaction for the in situ synthesis of a chemotherapeutic agent, thereby achieving targeted dual-agent combination therapy. We designed and synthesized a tetranuclear Cu(I) complex (Cu4) with remarkable cytotoxicity and notable catalytic ability for the in situ synthesis of a chemotherapeutic agent via Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC). We also constructed an apoferritin (AFt)-Cu4 nanoparticles (NPs) delivery system. AFt-Cu4 NPs not only showed an enhanced performance of tumor growth inhibition, but also improved the targeting ability and reduced the systemic toxicity of Cu4 in vivo. Importantly, the anticancer effect was enhanced by combining the AFt-Cu4 NPs with the resveratrol analogue obtained from the CuAAC reaction in situ. Finally, we revealed the anticancer mechanism of the Cu4/AFt-Cu4 NPs, which involves both cuproptosis and cuproptosis-induced systemic immune response.

Therapeutic Antibodies in Cancer Therapy.

The therapeutic arsenal in solid tumors comprises different anticancer strategies with diverse chemotherapeutic agents and a growing number of biological substances. Large clinical study-based chemotherapeutic protocols combined with biologicals have become an important component in (neo-) adjuvant therapy alongside surgery in solid cancers as well as radiation therapy in some instances. In recent years, monoclonal antibodies have entered the mainstream of cancer therapy. Their first use was as antagonists of oncogenic receptor tyrosine kinases, but today monoclonal antibodies have emerged as long-sought vehicles for the targeted delivery of potent chemotherapeutic agents and as powerful tools to manipulate anticancer immune responses. There is a growing number of FDA approved monoclonal antibodies and small molecules targeting specific types of cancer suggestive of the clinical relevance of this approach.Targeted cancer therapies , also referred to as personalized medicine, are being studied for use alone, in combination with other targeted therapies, and in combination with chemotherapy. The use of monoclonal antibodies in colorectal and gastric cancer for example have shown best outcome when combined with chemotherapy, even though single agent anti-EGFR antibodies seem to be active in particular setting of metastatic colorectal cancer patients. However, it is not well defined whether the addition of anti-VEGF - and anti-EGFR strategies to chemotherapy could improve outcome in those patients susceptible to colorectal cancer-related metastases resection. Among the most promising approaches to activating therapeutic antitumor immunity is the blockade of immune checkpoints, exemplified by the recently FDA-approved agent, Ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of Ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. This section attempts to discuss recent progress of targeted agents and in tackling a more general target applicable to gastrointestinal cancer .

Enhancing the anticancer immune response with the assistance of drug repurposing and delivery systems.

BACKGROUND: The immune system plays a pivotal role in the initiation, evolution, invasion and metastasis of cancer. Therapeutics aiming at modulating or boosting anticancer immune responses have experienced immense advances during the past decades, for example, anti-PD-1/PD-L1 monoclonal antibodies. MAIN BODY: Concomitant with advancements in the understanding of novel mechanisms of action, conventional or emerging drugs bearing the potential to be repurposed for enhancing anticancer immunity have been identified. Meanwhile, ongoing advances in drug delivery systems enable us to utilise novel therapeutic strategies and impart drugs with fresh modes of action in tumour immunology. CONCLUSION: Herein, we systemically review these kinds of drugs and delivery systems that can unleash the anticancer response through various aspects, including immune recognition, activation, infiltration and tumour killing. We also discuss the current caveats and future directions of these emerging strategies.

Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma.

PURPOSE: Sonodynamic therapy (SDT) is emerging as a cancer treatment alternative with significant advantages over conventional therapies, including its minimally invasive and site-specific nature, its radical antitumour efficacy with minimal side effects, and its capacity to raise an antitumour immune response. The study explores the efficacy of SDT in combination with nanotechnology against pancreatic ductal adenocarcinoma. METHODS: A nanoparticulate formulation (HPNP) based on a cathepsin B-degradable glutamate-tyrosine co-polymer that carries hematoporphyrin was used in this study for the SDT-based treatment of PDAC. Cathepsin B levels in BxPC-3 and PANC-1 cells were correlated to cellular uptake of HPNP. The HPNP efficiency to induce a sonodynamic effect at varying ultrasound parameters, and at different oxygenation and pH conditions, was investigated. The biodistribution, tumour accumulation profile, and antitumour efficacy of HPNP in SDT were examined in immunocompetent mice carrying bilateral ectopic murine pancreatic tumours. The immune response profile of excised tumour tissues was also examined. RESULTS: The HPNP formulation significantly improved cellular uptake of hematoporphyrin for both BxPC-3 and PANC-1 cells, while increase of cellular uptake was positively correlated in PANC-1 cells. There was a clear SDT-induced cytotoxicity at the ultrasound conditions tested, and the treatment impaired the capacity of both BxPC-3 and PANC-1 cells to form colonies. The overall acoustic energy and pulse length, rather than the power density, were key in eliciting the effects observed in vitro. The SDT treatment in combination with HPNP resulted in 21% and 27% reduction of the target and off-target tumour volumes, respectively, within 24 h. A single SDT treatment elicited an antitumour effect that was characterized by an SDT-induced decrease in immunosuppressive T cell phenotypes. CONCLUSION: SDT has significant potential to serve as a monotherapy or adjunctive treatment for inoperable or borderline resectable PDAC.

PARP1 inhibition elicits immune responses against non-small cell lung cancer.

High levels of intracellular poly(ADP-ribose) (PAR) resulting from an elevated activity of PAR polymerase-1 (PARP1) correlate with poor infiltration of non-small cell lung cancers by cytotoxic T lymphocytes and dismal patient prognosis. Preclinical experimentation now demonstrates that PARP1 inhibition in cancer cells mediates strong immunostimulatory effects.

The role of Platinum(IV)-based antitumor drugs and the anticancer immune response in medicinal inorganic chemistry. A systematic review from 2017 to 2022.

Platinum-based antitumor drugs have been used in many types of tumors due to its broad antitumor spectrum in clinic. Encouraged by the cisplatin's (CDDP) worldwide success in cancer chemotherapy, the research in platinum-based antitumor drugs has evolved from traditional platinum drug to multi-ligand and multifunctional platinum prodrugs over half a century. With the rapid development of metal drugs and the anticancer immune response, challenges and opportunities in platinum drug research have been shifted from traditional platinum-based drugs to platinum-based hybrids and the direction of development is tending toward photodynamic therapy, nano-delivery therapy, drug combination, targeted therapy, diagnostic therapy, immune-combination therapy and tumor stem cell therapy. In this review, we first exhaustively overviewed the role of platinum-based antitumor prodrugs and the anticancer immune response in medicinal inorganic chemistry based on the special nanomaterials, the modification of specific ligands, and the multiple functions obtained that are beneficial for tumor therapy in the last five years. We also categorized them according to drug potency and function. There hasn't been a comprehensive evaluation of precursor platinum drugs in prior articles. And a multifarious approach to distinguish and detail the variety of alterations of platinum-based precursors in various valence states also hasn't been summarized. In addition, this review points out the main problems at the interface of chemistry, biology, and medicine from their action mechanisms for current platinum drug development, and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks. And a promising idea is also enlightened for researchers in the development and discovery of platinum prodrugs.

Cancer-activated doxorubicin prodrug nanoparticles induce preferential immune response with minimal doxorubicin-related toxicity.

The effective chemotherapeutic drug, doxorubicin (DOX), elicits immunogenic cell death (ICD) and additional anticancer immune responses during chemotherapy. However, it also induces severe side effects and systemic immunosuppression, hampering its wide clinical application. Herein, we constructed cancer-activated DOX prodrug by conjugating the cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in FRRG-DOX that self-assembled into cancer-activated DOX prodrug nanoparticles (CAP-NPs). The resulting CAP-NPs were further stabilized with the FDA-approved compound, Pluronic F68. CAP-NPs formed stable prodrug nanoparticles and they were specifically cleaved to cytotoxic DOX molecules only in cathepsin B-overexpressing cancer cells, inducing a cancer cell-specific cytotoxicity. In particular, the CAP-NPs induced ICD through cathepsin B-cleavage mechanism only in targeted cancer cells in vitro. In colon tumor-bearing mice, selectively accumulated CAP-NPs at tumors enhanced antitumor immunity without DOX-related severe toxicity, inflammatory response and systemic immunosuppression. Moreover, cytotoxicity against immune cells infiltrated into tumor microenvironment was significantly reduced compared to free DOX, leading to increased response to checkpoint inhibitor immunotherapy. The combinatorial treatment of CAP-NPs with anti-PD-L1 exhibited high rate of complete tumor regression (50%) compared to free DOX with anti-PD-L1. Concurrently, DOX-related side effects were greatly reduced during chemoimmunotherapy. Collectively, our results suggest that cancer-activated DOX prodrug nanoparticles provide a promising approach to increase clinical benefit by inducing an immune response preferentially only to targeted cancer cells, not to normal cells and immune cells, and potentiates checkpoint inhibitor immunotherapy.

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation.

Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.

Hyperthermic intra-peritoneal chemotherapy and anticancer immune response.

Peritoneal carcinomatosis (PC) is a metastatic disease of primary tumors localized in the abdomen. Although this disease is considered a terminal condition, recent treatments combining surgery with heated intra-peritoneal chemotherapy (HIPEC) significantly increase patient survival. We have determined that the protective effect of HIPEC is partially linked to the induction of an efficient anticancer immune response.

Personalized dendritic cell-based tumor immunotherapy.

Advances in the understanding of the immunoregulatory functions of dendritic cells (DCs) in animal models and humans have led to their exploitation as anticancer vaccines. Although DC-based immunotherapy has proven clinically safe and efficient to induce tumor-specific immune responses, only a limited number of objective clinical responses have been reported in cancer patients. These relatively disappointing results have prompted the evaluation of multiple approaches to improve the efficacy of DC vaccines. The topic of this review focuses on personalized DC-based anticancer vaccines, which in theory have the potential to present to the host immune system the entire repertoire of antigens harbored by autologous tumor cells. We also discuss the implementation of these vaccines in cancer therapeutic strategies, their limitations and the future challenges for effective immunotherapy against cancer.