Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently. 

Exploring treatment options in cancer: Tumor treatment strategies

Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.

/pdf/tumor-infiltrating-lymphocytes-for-treatment-of-solid-tumors-3puugarh.pdf

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

Abstract The incidence and mortality of cancer are the major health issue worldwide. Apart from the treatments developed to date, the unsatisfactory therapeutic effects of cancers have not been addressed by broadening the toolbox. The advent of immunotherapy has ushered in a new era in the treatments of solid tumors, but remains limited and requires breaking adverse effects. Meanwhile, the development of advanced technologies can be further boosted by gene analysis and manipulation at the molecular level. The advent of cutting-edge genome editing technology, especially clustered regularly interspaced short palindromic repeats (CRISPR-Cas9), has demonstrated its potential to break the limits of immunotherapy in cancers. In this review, the mechanism of CRISPR-Cas9-mediated genome editing and a powerful CRISPR toolbox are introduced. Furthermore, we focus on reviewing the impact of CRISPR-induced double-strand breaks (DSBs) on cancer immunotherapy (knockout or knockin). Finally, we discuss the CRISPR-Cas9-based genome-wide screening for target identification, emphasis the potential of spatial CRISPR genomics, and present the comprehensive application and challenges in basic research, translational medicine and clinics of CRISPR-Cas9. 

/pdf/recent-advances-and-applications-of-crispr-cas9-in-cancer-3dj957ho.pdf

Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy

Oncolytic viruses (OVs) as one promising antitumor methods have made important contributions to tumor immunotherapy, which arouse increasing attention. They provide the dual mechanisms including direct killing effect toward tumor cells and immune activation for elevating antitumor responses, which have been proved in many preclinical studies. Especially, natural or genetically modified viruses as clinical immune preparations have emerged as a new promising approach objective to oncology treatment. The approval of talimogene laherparepvec (T-VEC) by the U.S. Food and Drug Administration (FDA) for the therapy of advanced melanoma could be considered as a milestone achievement in the clinical translation of OV. In this review, we first discussed the antitumor mechanisms of OVs with an emphasis on targeting, replication, and propagation. We further outlined the state of the art of current OVs in tumor and underlined the activated biological effects especially including immunity. More significantly, the enhanced immune responses based on OVs were systematically discussed from different perspectives such as combination with immunotherapy, genetic engineering of OVs, integration with nanobiotechnology or nanoparticles, and antiviral response counteraction, where their principles were shed light on. The development of OVs in the clinics was also highlighted to analyze the actuality and concerns of different OV applications in clinical trials. At last, the future perspectives and challenges of OVs as an already widely accepted treatment means were discussed. This review will provide a systematic review and deep insight into OV development and also offer new opportunities and guidance pathways to drive the further clinical translation.

Emerging Nano-/Biotechnology Drives Oncolytic Virus-Activated and Combined Cancer Immunotherapy

http://www.cell.com/article/S1525001622003707/pdf

An armed oncolytic virus enhances the efficacy of tumor-infiltrating lymphocyte therapy by converting tumors to artificial antigen presenting cells in situ.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers worldwide. Despite the promising outcome of immune checkpoint inhibitors and agonist antibody therapies in different malignancies, PDAC exhibits high resistance due to its immunosuppressive tumor microenvironment (TME). Ameliorating the TME is thus a rational strategy for PDAC therapy. The intratumoral application of oncolytic herpes simplex virus-1 (oHSV) upregulates pro-inflammatory macrophages and lymphocytes in TME, and enhances the responsiveness of PDAC to immunotherapy. However, the antitumor activity of oHSV remains to be maximized. The aim of this study is to investigate the effect of the CD40L armed oHSV on the tumor immune microenvironment, and ultimately prolong the survival of the PDAC mouse model. Methods The membrane-bound form of murine CD40L was engineered into oHSV by CRISPR/Cas9-based gene editing. oHSV-CD40L induced cytopathic effect and immunogenic cell death were determined by microscopy and flow cytometry. The expression and function of oHSV-CD40L was assessed by reporter cell assay. The oHSV-CD40L was administrated intratumorally to the immune competent syngeneic PDAC mouse model, and the leukocytes in TME and tumor-draining lymph node were analyzed by multicolor flow cytometry. Intratumoral cytokines were determined by ELISA. Results Intratumoral application of oHSV-CD40L efficiently restrained the tumor growth and prolonged the survival of the PDAC mouse model. In TME, oHSV-CD40L-treated tumor accommodated more maturated dendritic cells (DCs), which in turn activated T helper 1 and cytotoxic CD8+ T cells in an interferon-γ-dependent and interleukin-12-dependent manner. In contrast, the regulatory T cells were significantly reduced in TME by oHSV-CD40L treatment. Repeated dosing and combinational therapy extended the lifespan of PDAC mice. Conclusion CD40L-armed oncolytic therapy endues TME with increased DCs maturation and DC-dependent activation of cytotoxic T cells, and significantly prolongs the survival of the model mice. This study may lead to the understanding and development of oHSV-CD40L as a therapy for PDAC in synergy with immune checkpoint blockade.

/pdf/cd40l-armed-oncolytic-herpes-simplex-virus-suppresses-1cikge8h.pdf

CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model

Despite the promise in whole‐tumor cell vaccines, a key challenge is to overcome the lack of costimulatory signals. Here, agonistic‐antibody‐boosted tumor cell nanovaccines are reported by genetically engineered antibody‐anchored membrane (AAM) technology, capable of effectively activating costimulatory pathways. Specifically, the AAM can be stably constructed following genetic engineering of tumor cell membranes with anti‐CD40 single chain variable fragment (scFv), an agonistic antibody to induce costimulatory signals. The nanovaccines are versatilely designed and obtained based on the anti‐CD40 scFv‐anchored membrane and nanotechnology. Following vaccination, the anti‐CD40 scFv‐anchored membrane nanovaccine (Nano‐AAM/CD40) significantly facilitates dendritic cell maturation in CD40‐humanized transgenic mice and subsequent adaptive immune responses. Compared to membrane‐based nanovaccines alone, the enhanced antitumor efficacy in both “hot” and “cold” tumor models of the Nano‐AAM/CD40 demonstrates the importance of agonistic antibodies in development of tumor‐cell‐based vaccines. To expand the design of nanovaccines, further incorporation of cell lysates into the Nano‐AAM/CD40 to conceptually construct tumor cell‐like nanovaccines results in boosted immune responses and improved antitumor efficacy against malignant tumors inoculated into CD40‐humanized transgenic mice. Overall, this genetically engineered AAM technology provides a versatile design of nanovaccines by incorporation of tumor‐cell‐based components and agonistic antibodies of costimulatory immune checkpoints.

Tumor Cell Nanovaccines Based on Genetically Engineered Antibody‐Anchored Membrane

Department of Pharmacy, e First A liated Hospital of Hainan Medical University, Haikou 571000, China Reproductive Medicine Center, Women and Children Medical Center of Hainan Province, Haikou 571000, China Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, Haikou 571199, China Department of Pharmacy, Yongzhou Central Hospital, Yongzhou 425000, China

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An armed oncolytic virus enhances the efficacy of tumor-infiltrating lymphocyte therapy by converting tumors to artificial antigen presenting cells in situ.

CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model

Tumor Cell Nanovaccines Based on Genetically Engineered Antibody‐Anchored Membrane

Metabonomics Coupled with Network Pharmacology