Advanced Strategies of CAR-T Cell Therapy in Solid Tumors and Hematological Malignancies.

Chimeric antigen receptor T-cells, known as CAR-T cells, represent a promising breakthrough in the realm of adoptive cell therapy. These T-cells are genetically engineered to carry chimeric antigen receptors that specifically target tumors. They have achieved notable success in the treatment of blood-related cancers, breathing new life into this field of medical research. However, numerous obstacles limit chimeric antigen receptors T-cell therapy's efficacy, such as it cannot survive in the body long. It is prone to fatigue and exhaustion, leading to difficult tumor elimination and repeated recurrence, affecting solid tumors and hematological malignancies. The challenges posed by solid tumors, especially in the context of the complex solid-tumor microenvironment, require specific strategies. This review outlines recent advancements in improving chimeric antigen receptors T-cell therapy by focusing on the chimeric antigen receptors protein, modifying T-cells, and optimizing the interaction between T-cells and other components within the tumor microenvironment. This article aims to provide an extensive summary of the latest discoveries regarding CAR-T cell therapy, encompassing its application across various types of human cancers. Moreover, it will delve into the obstacles that have emerged in recent times, offering insights into the challenges faced by this innovative approach. Finally, it highlights novel therapeutic options in treating hematological and solid malignancies with chimeric antigen receptors T-cell therapies.

Engineering siRNA therapeutics: challenges and strategies.

Small interfering RNA (siRNA) is a potential method of gene silencing to target specific genes. Although the U.S. Food and Drug Administration (FDA) has approved multiple siRNA-based therapeutics, many biological barriers limit their use for treating diseases. Such limitations include challenges concerning systemic or local administration, short half-life, rapid clearance rates, nonspecific binding, cell membrane penetration inability, ineffective endosomal escape, pH sensitivity, endonuclease degradation, immunological responses, and intracellular trafficking. To overcome these barriers, various strategies have been developed to stabilize siRNA, ensuring their delivery to the target site. Chemical modifications implemented with nucleotides or the phosphate backbone can reduce off-target binding and immune stimulation. Encapsulation or formulation can protect siRNA from endonuclease degradation and enhance cellular uptake while promoting endosomal escape. Additionally, various techniques such as viral vectors, aptamers, cell-penetrating peptides, liposomes, and polymers have been developed for delivering siRNA, greatly improving their bioavailability and therapeutic potential.

Association analysis and allelic distribution of deletion in CC chemokine receptor 5 gene (CCR5Δ32) among breast cancer patients of Pakistan.

Chemokine CC receptor type 5 (CCR5) is a cell surface receptor that has high affinity for chemotropic cytokines called chemokines. The CCR5 gene contains a 32 base pairs (bp) deletion (CCR5Δ32). This deletion may result in a malformed and nonfunctional receptor, reported to be responsible for the development and dissemination of different cancers. CCR5Δ32 exists in two allelic forms i.e. deletion (D) and wild type (WT). This study aims to detect the role of CCR5Δ32 in breast cancer development. Blood samples were collected from breast cancer patients (330) and controls of same gender (306). Along with this histopathologically diagnosed malignant tissue samples were also excised from breast lesions of 100 patients. Genetic variations within the blood and tissue samples were examined by PCR then observed through gel electrophoresis and confirmed by direct DNA sequencing. Obtained DNA sequences were aligned and analyzed by MEGA6 software. Genotypic and association analyses were done by SPSS software version 17.0. Deletion of 32 bp in CCR5 gene has been analyzed. Genotypic variations of CCR5Δ32 are; homozygous wild type (WT/WT), heterozygous deletion (WT/D) and homozygous deletion (D/D). Statistical analyses of CCR5Δ32 data revealed that WT/D was significantly higher in blood samples of breast cancer patients (7.27% (24/330)) as compare to controls (1.30% (4/306)). In tumor tissue samples WT/WT being the most frequent genotype (99.00% (99/100)) with 1.00 (1/100) of D/D which suggested that it may be acquired. Hence, association analysis showed that CCR5Δ32 is positively associated with breast cancer in Pakistan (p < 0.001). The risk ratio of CCR5Δ32 was 5.6610 (95% confidence interval: 2.0377 to 15.7267) and odds ratio was calculated to be 6.0335 (95% confidence interval: 2.1288 to 17.0999) which signifies that deletion also increases the risk of breast cancer development. Moreover, association analyses also revealed that clinicopathological features do not have any impact on the CCR5Δ32 genotype of breast cancer. This suggests that deletion of 32 bp in CCR5 gene may be associated with breast cancer. CCR5 signals the activation and migration of immune cells at the site of tumor formation. Because of deletion; deformed CCR5 receptor might be unable to express and function properly which may subdue the immunity against cancer hence, leading to its progression.