Let's talk about cell therapy and the processes involved

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Even though chimeric antigen receptor (CAR) T-cell therapies have helped patients in undeniable ways, autologous cell therapies made in centralized production facilities have problems that make them hard to use for a large number of people. Allogeneic or "off-the-shelf" versions are one possible solution, but the people who make them have to deal with problems like graft-versus-host disease, the possibility of introducing chromosomal abnormalities, making sure that all donor cells have their genes successfully edited, and problems with T-cell exhaustion.

Making autologous therapies available at the point of service is another viable choice (POC). To produce CAR T-cell therapies by good manufacturing practice, companies like Miltenyi Biotech, Lonza, SQZ Biotech, Orgenesis, and Ori Biotech have created or are creating closed, automated cell- and gene-therapy production platforms with small footprints that can be installed in hospitals and institutions (GMP). Several research institutions are investigating the potential of such devices. Orgenesis and aCGT Vector, each with their methods of production and POC site networks, are both in the works.

Some businesses are investigating a third approach that would do away with ex vivo genome editing of immune cells. These conditions are ideal for the development of CAR cells inside the human body. This method has its problems, but it might be able to combine the good things about both autologous and allogeneic cell treatments.

Autologous problems

In today's medical world, autologous cell treatments call for the extraction of immune cells from the patient, which are then sent to a centralized manufacturing facility. The majority of patients suffer from severe illnesses and have been subjected to different treatments in the past, which results in variability in the beginning material and the possibility of manufacturing malfunctions. There are only so many production slots, so there are often delays, which people with long-term illnesses usually can't afford. Because there are a limited number of facilities that offer cell therapy, patients must journey to these facilities to receive treatment. This places an additional strain on both the patients and their families. In addition, the costs associated with gene-modified cell treatments are quite expensive.

According to an IQVIA study, the top three reasons why community oncologists do not recommend patients for CAR-T therapy are the patient's health condition, the patient's expense, and the patient's travel distance. Gregory Frost, chairman and CEO of EXUMA Biotech, makes these points.

Allogeneic constraints

When it comes to certain conditions, allogenic cell therapies offer more convincing benefits than autologous CAR T-cell treatments. Because they are off-the-shelf products, they are available right away. This gets rid of the logistical problems that make autologous therapies take longer and cost more. Also, they don't have the inconsistency that usually comes with cells that come from a patient.

But, according to Frost, avoiding the immune system's natural response to foreign CAR-T cells has turned out to be much harder than getting past business problems like switching from rodent antibodies to human antibodies. According to him, "many different strategies are being looked into, but the only clinically validated solutions to this challenge to date have been sustained immunosuppressive treatment regimens to eliminate the body's T and NK cell function, which increases the risk of opportunistic infections without transplant-ward-level care." Even though many different strategies are being looked into, this is still the case. Because of this, patients and their families who don't live close to one of these specialized facilities have more problems because they usually have to stay longer in the place where they get specialized care. Also, this leads to the addition of new responsibilities.

Improving accessibility with internal CAR treatments

The advantages of both native and allogeneic treatments may be present in vivo CAR therapies. According to Frost, the most apparent benefit that in vivo CAR treatment could have over autologous or allogeneic cellular therapy is that it might combine the longevity of autologous cell therapy with the less expensive and easier-to-use nature of a pre-made product.

According to Frost, a CAR therapy with the same cost-of-goods-per-patient-treated as biologics could shift the efficacy threshold from a 30-50% increase in progression-free survival or overall survival, which is a crucial objective for solid tumours, to a 30+% improvement in these outcomes. Additionally, he adds, "lymphodepletion may not be required for in vivo therapies, meaning that care could be provided outside of tertiary care facilities with intensive care units and CAR therapy could be used for conditions like the autoimmune disease that have not previously been treated because the benefit-to-risk ratio was insufficient." Additionally, they do not have to deal with the challenging practicalities of freezing a cellular drug product because in vivo CAR treatment goods are ready to use.

Frost says that, in general, in vivo CAR treatment "may solve the most important problems with autologous and allogeneic gene-modified cell therapies." Additionally, it might make CAR therapy less expensive, safer, possibly more successful, and accessible in locations that are handier for patients and their families.

In vivo CAR/T-cell receptor (TCR) treatments, according to Frost, also facilitate cell processing confirmation. This is in addition to the therapy's possibility for use in a broader variety of care environments and the fact that it is less expensive and complicated. He says that the in vivo method "does not require the costs and time to build an optimized and verified production cell process, which can cause new problems if the process changes in the future, even though the result is the process."

Additionally, according to Frost, the vector's transduction program can be readily enhanced and modified in minor ways. This enables repeated testing of the vector before its application to a person. Because the technology is so adaptable, he predicts that universities and both small and big biotechnology businesses will use it. This could lead to a much faster and more affordable process for developing revolutionary treatments.

In-vivo technological difficulties

In vivo, gene-modified cell therapies undoubtedly have their unique collection of technological difficulties. Frost says that it is a big problem that the patient is not prepared for the injection of the engineered cells by having lymphodepletion done first. This process gets rid of immune cells that would compete with CAR cells for growth factors and other nutrients. This makes it less likely that the CAR cells will live, grow, and work as an antitumor agent. Since lymphodepletion would get rid of the cells that are supposed to be used for in vivo engineering, it is not a good option for in vivo CAR treatment. Frost says that because of this, any in vivo strategy will need a way to guarantee strong growth and long life in an environment where there is fierce competition for the same nutrients.

To successfully reengineer the immune cells of interest, the way the genetic material is sent to the cells must be very specific. Frost says that to avoid unintended gene changes, the method of transport must specifically target the type of cell that is to be re-engineered (e.g., T cell, natural killer cell). This is true regardless of whether the carrier is a viral vector or lipid nanoparticle (LNP).

Approaches in vivo that are viral and nonviral
In vivo engineering is being studied using two distinct methods, viral vectors and lipid nanoparticles. Viral methods are usually based on the same retroviral vectors used in contemporary ex vivo cellular treatments, whereas nonviral approaches typically involve LNPs encapsulating nucleic acids.

According to Frost, non-viral methods may have the benefit of a more clearly defined regulatory route as a result of the COVID-19 vaccines' recent authorization. Given that CAR transcripts are diluted (and ultimately lost) as the cells proliferate, he notes, non-integrating methods might not, however, result in a long-lasting clinical reaction.

In the lack of a clinical reaction, such treatments would probably necessitate persistent retreatment, particularly when treating solid tumours, which demand a protracted T-cell response. Incorporating lentiviral (LV) vectors, for example, may provide the advantage of reliably

to enable a prolonged reaction from a single dosage by integrating into the host-cell genome," explains Frost. As a result, he expects more research into the viral tropism of methods to lessen the risks of negative outcomes related to non-target cell integration.

#A possible regulatory route plan for gene therapy
In vivo, gene-modified cell therapies are related to direct gene therapies, some of which have already been approved by the governments of the US, the EU, and other countries, even though they are a new type of medicine. According to Frost, these gene therapy decisions can help with the regulatory assessment of in vivo CAR treatments. "Each product and technology has its unique factors that must be taken into account for a specific indication," he says. "However, the FDA has also put out many guideline papers about gene therapy that can help sponsors make in vivo gene treatments."

Frost thinks that regulators will require developers of in vivo therapies based on retroviral vectors to show that the vectors are transducing the target cell type (such as T cells) and not other cell types, such as hematopoietic stem cells or gametes. This is like how regulators have recently looked at retroviral gene vectors in cells other than T lymphocytes. In this context, he points out that the tropism of the transport vehicle—viral or non-viral—must be carefully taken into account.

Frost predicts that applicants will begin clinical trials
within the next few years given the increasing number of businesses creating in vivo CAR therapies using a variety of methods. The information obtained from those experiments will help to improve the research. "It can be anticipated that the industry as a whole will become more familiar with in vivo gene therapy as a result of the advancements that will be made and the increasing body of evidence that will be produced as a result of these studies, ultimately enabling the growth of other products to the clinic and eventually on the market. Monoclonal antibodies, which were first found in 1975 and were first approved in 1986, have been used in many different ways and have been improved in many different ways. This suggests that in vivo CAR therapy might be possible. He concludes that this technology will be much easier to make with the knowledge and technology we have now.



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