Exploring treatment options in cancer: Tumor treatment strategies

Abstract

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.

Fig. 1

The milestone of cancer therapy development. This timeline illustrates the significant advancements in cancer therapy over the past 170 year. Beginning with the adoption of general anesthesia for surgical procedures in the mid-1800s and the groundbreaking invention of X-rays by Wilhelm Conrad Röntgen in the late 19th century, which paved the way for radiation therapy combined with surgery, the field of oncology has witnessed a series of transformative treatments.Key developments include the introduction of chemotherapy during World War II, the advent of immunotherapy, and the more recent progress in gene therapy. The 1990s marked a turning point with the FDA approval of BCG for bladder cancer treatment and Rituximab for B-cell lymphomas, initiating the era of targeted therapies. Trastuzumab and Imatinib further revolutionized the treatment of breast cancer and chronic myeloid leukemia, respectively. The new millennium brought targeted therapies for non-small cell lung cancer with drugs like Gefitinib and Erlotinib, and the first anti-angiogenic drug, Bevacizumab, which targeted tumor blood supply. Rigvir’s approval in Latvia for melanoma treatment signified the global reach of cancer advancements. The successful application of CAR-T cell therapy by Carl June in 2011 and the FDA approval of Pembrolizumab and Nivolumab in 2014 for melanoma treatment highlighted the potential of immunotherapy. Preventive measures also evolved, as evidenced by the approval of the nine-valent Gardasil 9 vaccine, offering broader protection against HPV strains linked to cervical cancer. The resurgence of oncolytic viruses was evident with the approval of T-VEC and Delytact for melanoma and malignant glioma, respectively. The 2020 s have introduced targeted therapies for KRAS gene mutations with Sotorasib and the combination of atezolizumab and bevacizumab as a preferred first-line treatment for hepatocellular carcinoma, as endorsed by the NCCN guidelines in 2021. This figure encapsulates the continuous innovation and dedication to enhancing cancer care, reflecting the dynamic nature of the fight against cancer and the pursuit of improved patient outcomes. This figure was created with Biorender.com

Fig. 2

Composition of ADCs and Mechanism of Action in Targeting Cells. a Composition of ADCs. ADCs are composed of an antibody, a linker, and a toxin. The antibody serves as the backbone of the ADC, required to conjugate with the other two components for specific targeted endocytosis within the human body. Therefore, the demands for this part include low immunogenicity and targeting specificity. The linker is the component within the system that connects the antibody to the toxin. The toxin, the element that ultimately kills the tumor, is attached to the linker and travels with the antibody to the target site to exert its effect. b Mechanism of Action of ADCs Targeting Cells. ADCs exert their therapeutic effects through a process that begins with the specific binding of the antibody component of the ADC to antigens on the surface of tumor cells. Upon binding, the ADCs trigger endocytosis, a cellular process where large molecules are internalized into vesicles. These vesicles, known as endosomes, mature by moving through the cell and eventually fuse with lysosomes, where the ADCs are broken down. The cytotoxic drug component, which is linked to the antibody via a cleavable or non-cleavable linker, is then released into the lysosome or directly into the cytoplasm, where it exerts its toxic effects on the tumor cell, leading to cell death. In some cases, the released drug can also affect neighboring tumor cells through a bystander effect, enhancing the overall therapeutic impact. c The five core elements that influence the effectiveness of ADCs. The table outlines the requirements for various components and synthesis processes of ADC. Initially, the selection of ADC antigen substances must prioritize high specificity and low exfoliative and endocytic effects to ensure targeted action. The antibody, a key component of ADCs, demands high affinity, rapid internalization, low immunogenicity, and reliance on ADCC (Antibody-Dependent Cellular Cytotoxicity) and CDC (Complement-Dependent Cytotoxicity) mechanisms, along with a prolonged half-life for effective targeting and action. The linker should exhibit high stability to prevent rupture during circulation, enable specific release in the target area, and be hydrophilic and degradable for bystander effects. The toxin should have potent cytotoxicity, the ability to undergo structural remodeling, a clear mechanism of action, resistance to degradation within cells, strong hydrophobicity for membrane permeability to induce bystander effects, and a short half-life. The coupling method affects drug uniformity and loading, requiring optimal DAR (Drug-Antibody Ratio) values and the implementation of site-specific conjugation strategies. This figure was created with Biorender.com

Fig. 3

The composition and generation of CAR-T. a Illustrates the structure and mechanism of action of a Chimeric Antigen Receptor (CAR). The CAR is composed of three main domains: the extracellular domain, which includes the antigen recognition domain (scFv) and the hinge region; the transmembrane domain that anchors the receptor in the cell membrane; and the intracellular domain responsible for signaling. The scFv is engineered to recognize specific tumor-associated antigens, such as CD19, CD20, and CD22. The hinge region allows for flexibility in the CAR’s structure, while the transmembrane domain links the extracellular recognition capabilities to the intracellular signaling pathways. The intracellular domain typically contains co-stimulatory motifs that enhance T cell activation upon antigen recognition. b The therapeutic process of CAR-. Genetically engineered CAR-T cells are infused into the patient, where they specifically recognize and bind to tumor antigens via their CARs. This interaction leads to the activation of the CAR-T cells and the release of cytotoxic molecules, such as perforin and granzyme B, which induce apoptosis in the tumor cells. c The evolution of CAR-T. It outlines the five generations of CAR-T cell development. First-generation CAR-T cells had basic signaling domains but lacked co-stimulatory signals, resulting in limited in vivo proliferation and clinical efficacy. Second-generation CAR-T cells included additional co-stimulatory domains, significantly improving their potency and persistence. Third-generation CAR-T cells further enhanced tumor lysis and cytokine secretion by incorporating dual co-stimulatory molecules. Fourth-generation CAR-T cells were designed with controllable suicide genes and pro-inflammatory cytokines for enhanced solid tumor targeting. Fifth-generation CAR-T cells, or “off-the-shelf” universal CAR-T cells, are created by CRISPR/Cas9 gene editing to generate allogeneic T cells, addressing potential GVHD issues. This figure was created with Biorender.com

Fig. 4

The challenges and strategies about CAR-T cell therapy. The main challenges currently faced in CAR-T therapy include: Antigenic drift, Systemic cytokine toxicities, Lack of effective targets for solid tumors, Tumor microenvironment suppression and epitope expansion, Tumor barrier, Graft-versus-host disease (GVHD), and Host immune rejection, along with their corresponding primary solutions. This figure was created with Biorender.com

Fig. 5

Other kind of cell therapy. a Preparation of CAR-NK and the mechanisms of CAR-NK cell. The preparation of CAR-NK cells involves isolating NK cells from sources such as umbilical cord blood or hematopoietic stem cells, followed by genetic modification to integrate a CAR construct that includes an antigen recognition domain. These cells are then expanded in vitro before being infused back into the patient. Once in the body, CAR-NK cells utilize their CAR to recognize and bind to specific tumor antigens, leading to their activation and the subsequent release of cytotoxic granules and cytokines to eliminate cancer cells. Additionally, the Fc receptor CD16 on NK cells can mediate ADCC, further enhancing their tumoricidal activity. b Preparation of TIL. The preparation of tumor-infiltrating lymphocytes (TIL) involves isolating immune cells from a patient’s tumor tissue, where they have naturally infiltrated. The process typically includes surgical removal of the tumor mass, followed by the mechanical and enzymatic dissociation of the tissue to obtain a single-cell suspension. The cells are then cultured in vitro, and the TILs, which are often CD8+ T cells, are selectively expanded through various techniques, such as interleukin-2 (IL-2) stimulation. Once a sufficient number of TILs are obtained, they are infused back into the patient as part of the adoptive cell transfer therapy, aiming to boost the immune system’s ability to target and destroy cancer cells. c The structure comparation between TCR-T and CAR-T. TCR-T cells are genetically modified to express a specific T-cell receptor that recognizes MHC-presented antigens, allowing them to target a broad range of tumor-associated antigens, including those derived from intracellular proteins. In contrast, CAR-T cells are engineered to express a chimeric antigen receptor that includes an antibody-derived antigen-binding domain, enabling them to target cell surface antigens without MHC restriction. d The overview of CAR-M (workflow and generation). Once inside the patient’s body, the CAR-M cells use their CAR to identify and attach to tumor cells, which triggers the activation of the macrophages, leading to the subsequent engulfment and destruction of the tumor cells. Additionally, they secrete pro-inflammatory cytokines that recruit other cells from the immune microenvironment to join in the attack against the tumor. CAR-Ms are differentiated into first and second generations. The second generation includes an extra CD3 domain compared to the first, endowing it with enhanced pro-inflammatory properties and sustained M1 macrophage activation. This figure was created with Biorender.com

Fig. 6

Various modes of genome editing. a ZFNs: By designing multiple zinc finger proteins to bind with specific DNA sequences, they guide the nuclease to cut the target gene, achieving precise gene editing through NHEJ and HDR. b TALENs: Specific transcription activator-like effector molecules are fused with nuclease domains. Two TALEN modules are necessary to bind to the target site, with a FokI nuclease fused to the DNA-binding domains, enabling precise gene editing through NHEJ and HDR. c CRISPR-Cas9: This system employs the Cas9 protein, guided by RNA molecules, to enable precise DNA cleavage at specific target sequences. It achieves accurate gene editing through NHEJ and HDR. d Base editing: an advanced form of Cas genome editing that enables the substitution of specific bases without inducing double-stranded breaks. This technique is categorized into two main types: C•G to T•A Base Editors (CBEs) and A•T to G•C Base Editors (ABEs). e Prime editing: The procedure involves constructing a prime editor complex, which includes a Cas domain, an RT (reverse transcriptase) domain, and a pegRNA. This complex searches for the DNA segment containing the target mutation and introduces a nick just in front of the mutation site. The nicked DNA strand then serves as a primer for DNA synthesis within the RT complex. The corrected, nicked strand is preferentially used over the original diseased strand, and the cell’s natural DNA repair mechanisms subsequently remove the diseased strand. This figure was created with Biorender.com

Fig. 7

The process of cancer vaccine development. The preparation of cancer vaccines is a meticulous process involving multiple steps, aimed at developing vaccines that can stimulate the immune system to target cancer cells. This process begins with the selection and identification of specific tumor antigens, followed by the design of the vaccine, which may include peptides, recombinant proteins, genetic vectors, or dendritic cells. Subsequently, the vaccine undergoes immunological testing in vitro and is evaluated for its safety and efficacy in animal models. After successfully passing preclinical research, the vaccine proceeds to human clinical trials, including Phase I, II, and III trials, to assess its safety, immunogenicity, and therapeutic effectiveness. This figure was created with Biorender.com