in8bio: Innovative T Cell Therapies Redefined

Cell-based immunotherapies are transforming cancer treatment by harnessing the immune system to target and destroy malignant cells. Among these, T cell therapies offer durable responses in certain cancers, providing hope where traditional treatments fall short.

In8bio is advancing this field with innovative approaches that enhance T cell function and effectiveness. Their work focuses on leveraging unique T cell subsets to improve therapeutic outcomes.

Basic T Cell Functions

T cells are a key component of the adaptive immune system, distinguished by their ability to recognize specific antigens. Unlike innate immune cells, which provide broad-spectrum defense, T cells exhibit antigen specificity through their receptors (TCRs), enabling them to target distinct molecular signatures. This specificity arises from genetic recombination in the thymus, where immature T cells undergo selection to recognize foreign antigens while avoiding self-reactivity.

Once matured, T cells differentiate into subsets with distinct roles. CD4+ helper T cells coordinate immune responses by secreting cytokines that modulate B cells and macrophages, influencing antibody production, inflammation, and pathogen clearance. CD8+ cytotoxic T cells specialize in eliminating infected or abnormal cells by recognizing antigenic peptides on MHC class I molecules. Their cytotoxic function is mediated by perforin and granzymes, which induce apoptosis in target cells, preventing the spread of infection or malignant transformation.

Regulatory T cells (Tregs) maintain immune balance by suppressing excessive activation. They express FOXP3 and produce immunosuppressive cytokines like IL-10 and TGF-β, preventing autoimmune reactions. Disruptions in Treg function can lead to autoimmune diseases or chronic inflammation, highlighting the importance of balance between effector and regulatory T cells.

Role Of Gamma Delta T Cells In Immunology

Gamma delta (γδ) T cells bridge innate and adaptive immunity through unconventional antigen recognition and rapid response capabilities. Unlike conventional αβ T cells, which require MHC-mediated antigen presentation, γδ T cells detect a diverse array of antigens directly. This enables them to respond swiftly to infections, tissue damage, and malignant transformation. Their TCRs, composed of γ and δ chains, recognize stress-induced ligands, microbial metabolites, and phosphoantigens without reliance on antigen-presenting cells. This MHC independence allows them to function in tumors with MHC downregulation, where conventional immune surveillance is compromised.

Unlike αβ T cells, which primarily circulate in blood and lymphoid organs, γδ T cells are enriched in epithelial barriers such as the skin, lungs, and intestinal mucosa. This positioning makes them frontline defenders against pathogens and cellular abnormalities. In the gut, they recognize microbial-derived metabolites and modulate inflammation. In the skin, they contribute to wound healing and tissue repair by producing growth factors like keratinocyte growth factor (KGF) and insulin-like growth factor 1 (IGF-1).

Beyond immune surveillance, γδ T cells exhibit potent cytotoxic activity against transformed or infected cells. They secrete pro-inflammatory cytokines such as IFN-γ and TNF-α and induce apoptosis via perforin and granzyme release. Certain subsets, like Vγ9Vδ2 T cells, are particularly effective at recognizing phosphoantigens produced by tumor cells and microbial pathogens. This makes them promising candidates for cancer immunotherapy, with clinical trials showing encouraging results, particularly in hematologic malignancies and solid tumors with high mutational burdens.

Mechanisms Of Cytotoxicity

Cytotoxic T cells eliminate target cells through a precise sequence of molecular interactions. The process begins with the formation of an immunological synapse, a structured interface that facilitates direct communication between the T cell and its target. Adhesion molecules like LFA-1 bind to ICAM-1 on the target cell, securing the connection for focused delivery of cytotoxic molecules. Once aligned, signaling cascades trigger the polarization of cytotoxic granules toward the synapse, ensuring efficient release.

A hallmark of T cell-mediated killing is the release of cytotoxic granules containing specialized proteins that induce apoptosis. Perforin integrates into the target cell membrane, forming channels that allow granzyme entry. Granzyme B activates caspase-dependent apoptosis by cleaving procaspase-3, leading to DNA fragmentation and mitochondrial dysfunction. Granzyme A induces single-strand DNA breaks and disrupts mitochondrial integrity through a caspase-independent pathway, ensuring redundancy in cell death mechanisms.

Beyond granule-mediated apoptosis, cytotoxic T cells can induce cell death through death receptor signaling. Fas ligand (FasL) on the T cell engages Fas receptors on the target cell, triggering the extrinsic apoptotic pathway. This recruits the death-inducing signaling complex (DISC), activating caspase-8 and downstream effector caspases. Similarly, TRAIL binding to death receptors DR4 and DR5 initiates another apoptotic pathway, providing an alternative mechanism for eliminating resistant cells.

Adoptive Cell Transfer Process

Adoptive cell transfer (ACT) is an advanced immunotherapy that involves collecting, modifying, and reinfusing a patient’s or donor-derived T cells to enhance their ability to recognize and eliminate malignant cells. The process begins with isolating T cells from peripheral blood or tumor-infiltrating lymphocytes (TILs), followed by ex vivo expansion. Depending on the strategy, cells may be genetically modified to express chimeric antigen receptors (CARs) or optimized T cell receptors (TCRs) for tumor recognition, allowing them to bypass immune evasion mechanisms.

Once expanded to therapeutic quantities, the modified T cells undergo rigorous quality control testing for potency, viability, and safety. This includes screening for unwanted mutations, confirming antigen specificity, and assessing functionality through cytotoxicity assays. Before reinfusion, patients often receive a preparatory lymphodepleting regimen, typically involving chemotherapy, to reduce immune suppression and create a favorable environment for the infused cells to proliferate. The reinfused T cells then home to the tumor site, where they exert their effects through direct cytotoxicity and cytokine-mediated signaling, contributing to tumor regression.