Researchers and clinicians constantly adapt medical research and cancer treatment to overcome new challenges. When more traditional methods fail to fend off certain malignancies, patients can now turn to adoptive cell therapy as a new treatment option. Adoptive cell therapy involves the combination of human T cells with scientific enhancements to treat diseases the body isn’t adequately equipped to handle on its own.
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One way these cells can be modified is through artificially enhancing binding receptors on the surface of T cells. T cell receptorsare proteins on the outer surface of lymphocytes that recognize and bind to antigens. Antigens are unique protein identifiers that exist on the surface of pathogens and other cells.
Antigens and receptors function like a lock and key, each one only linking with its specific counterpart. Two T cell therapies involve the modification of receptors for cancer treatment: CAR T cell therapy and engineered TCR therapy.
Chimeric Antigen Receptors (CAR)
CAR T cell therapy involves genetically engineering T cells extracted from the patient to express entirely new receptor proteins called chimeric antigen receptors (CAR). These synthetic receptors are specifically designed to bind naturally occurring antigens on the surface of cancer cells without the need for antigen-presenting cells (APCs) to mediate activation. This enables patients to receive treatment for cancers the body could not effectively combat on its own.
CAR T Cell Function
There are currently six FDA approvedCAR T cell therapies accessible for clinical use. These therapies treat certain types of blood cancers, including B-cell lymphoma, mantle cell lymphoma, multiple myeloma, and leukemia.
Clinical trials are underway for other receptor-antigen combinations that could treat a wider range of cancers beyond blood cancers. As research continues and the Food and Drug Administration (FDA) approves more cell therapies, the scope of treatable cancers will steadily increase.
CAR T Cell Manufacturing
The specifics of creating CAR T cells depend on the desired product, but the general process is the same. Manufacturing CAR T cells starts with the extraction and isolation of human T lymphocytes. After collection, those cells must be purified, modified to express the CAR, multiplied through cell culture expansion, and reinfused back into the patient. The result is an army of primed CAR T cells ready to attack cancer cells.
CAR T Cell Therapy Limitations
As with all therapies, CAR T cell therapy has limitations. CAR T therapy’s applicability is currently limited to treating certain blood cancers. Its effectiveness against solid tumors has traditionally been limited due to a lack of known unique antigen markers that can be used to differentiate the cancer tissue from normal tissue definitively.
Another limitation is the potentially severe side effects that can occur from CAR T therapy. Patients must be closely monitored during treatment for signs of cytokine release syndrome (CRS) and neurological toxicity that can come on quickly and require immediate medical intervention to prevent long-term health consequences like organ dysfunction.
Finally, manufacturing CAR T therapy treatments is typically complex and expensive. Current methods of T cell collection and separation are slow and inconsistent, which is not ideal for clinical trials and therapies.
The manufacturing of these modified T cells is a major bottleneck, meaning the labor required to culture these cells restricts the frequency at which they can be used. It takes considerable time and money to safely and effectively extract and purify enough T cells for the effective treatment of just one patient.
T Cell Receptor Engineering (TCR)
Like CAR T cell therapy, engineered T cell receptor therapy involves treating cancer cells with the patient’s activated T lymphocytes. Both strategies give T cells new receptors to enable more effective targeting of cancer cells.
The difference between the two methods lies mainly in which antigens they can recognize and how they are activated. As mentioned above, CAR T cells are activated by binding directly to antigens on the surface of cancer cells. However, in engineered TCR therapy, the added receptors can only bind with antigens presented by the major histocompatibility complex (MHC) proteins of antigen presenting cells (APCs).
TCRCell Therapy Function
MHCs are a collection of surface proteins on APCs and other cells involved in the immune system response. MHCs bind and present protein fragments from foreign pathogens for T lymphocytes to recognize. This initiates a cascade of signaling pathways that ultimately results in T cell activation—these T cells then seek and destroy the corresponding tumor cell. By either selecting or engineering a cell’s TCR to better recognize a specific cancer antigen, TCR therapy greatly enhances the targeting of the reinfused T cells, leading to greater potential for positive patient outcomes.
TCR Manufacturing
The manufacturing process for TCR therapy is similar in many ways to that of CAR T cell therapy. T lymphocytes must be collected from the patient or acceptable donor and isolated from unwanted cells and debris.
Once purified, the T cells undergo selection for TCRs specific to the cancer. Then they are expanded, drastically increasing the amount of T cells. Once the cell count is sufficient, they go through quality control checks and are infused into the patient, where they are activated and trigger a cytotoxic response to the cancer.
TCR Therapy Limitations
When it comes to the difficulties and expenses of separating cells and cell manufacturing, engineered TCR therapy encounters the same issues as CAR T cell therapy. The time, labor, and equipment costs are high.
Additionally, TCR therapy relies on researchers and clinicians being able to select and find TCRs that adequately target the unique antigens for each patient. TCR therapy also tends to have more off-target effects since the antigen recognition process is not as selective as with CARs. However, TCR therapy still has the risk of severe side effects, including CRS.
TCR vs. CAR T
CAR T cell therapy and engineered TCR therapy represent two distinct adoptive cell therapy strategies, both aimed at modifying T cells to combat cancerous malignancies. While they share the common goal of harnessing the body’s immune system to target cancer cells, the mechanisms by which they recognize and attack these cells differ significantly.
The primary difference is in the type of receptor engineered into the T cells. CAR T cells are equipped with chimeric antigen receptors that enable them to directly recognize and bind to cancer cell antigens without the need for major histocompatibility complex presentation. In contrast, engineered TCR therapy enhances the natural TCRs to better recognize cancer antigens when they are presented by the MHC on tumor cells, making this approach MHC-dependent.
Benefits
In current immunotherapy research, TCR therapy is a more versatile method that can target more cancers. In contrast, CAR T therapy is more controlled and precise, although limited in the cancers it can target. However, research continues to advance CAR T cell therapy’s potential to target more cancers. Other related therapy strategies have also spun off with recent success—including CAR M (chimeric antigen receptor macrophage) therapy based on engineered macrophagecells, which has improved efficacy in solid tumors.
All of these methods allow clinical researchers to select and program receptors to target cancers that the body does not efficiently recognize. Once scientists identify the naturally occurring antigens on cancer cells, they can begin to build receptors that match them.
Between CAR T cell therapy and engineered T cell therapy, the ultimate goal is to develop treatment methods for as many cancers as possible while improving the manufacturing process for wider accessibility.
T Cell Separation
This research can be simplified by streamlining different portions of the manufacturing process. The separation of T cells requires a lot of time, and the equipment can be expensive. Traditionally, researchers have used complex machines to carry out the tedious task of sorting and purifying large volumes of lymphocytes.
Innovative cell separation strategies like Akadeum’s microbubble technology are more efficient and offer better results for a lower price. Microbubbles use buoyancy to quickly and carefully float target cells to the top of a sample, separating them from other substances.
Human T Cell Separation With BACS™ Microbubbles From Akadeum
Akadeum’s Human T Cell Isolation Kits allow for quick, gentle, and easy high throughput human T cell enrichment before cell sorting. The Akadeum team designed this technology to maintain the health and physiology of delicate cells of interest while maximizing retention, delivering a highly enriched population of target cells to enable better science. With Akadeum’s microbubbles, you can quickly and easily interrogate the full sample volume—directly in the sample container—using a fast and easy workflow.
Akadeum’s Human T Cell Leukopak Isolation Kit leverages novel microbubble technology to isolate truly untouched T cells directly from leukapheresis material without the need for lysis or density gradient centrifugation.
Akadeum’s Human T Cell Depletion Kit uses microbubbles to remove unedited T cells from CAR T cultures. This kit leaves a highly pure sample of engineered cells untouched and ready for downstream formulation.
Akadeum’s Human T Cell Selection, Activation, and Expansion Kit uses microbubbles to isolate highly pure populations of T cells and activate them for use in cell therapy workflows and assays. This immensely scalable process yields large quantities of highly activated and transducable cells needed to manufacture potent cell therapies.
If you work in cell isolation research, we’d love to hear from you! We are actively seeking new applications for our microbubble technology and would welcome the opportunity to learn more about your research to discover if our microbubbles can help you overcome long-standing hurdles in sample preparation.
Akadeum’s team of scientific experts is dedicated to the success of the researchers we work with. We are looking forward to equipping you with our novel microbubble technology as another tool at your disposal to unlock the next big scientific breakthrough.
