Cell and gene therapy

Cell and Gene Therapy

Cell and Gene Therapy is a family of therapeutic options that is experiencing rapid growth and acceptance both from regulators and clinical practitioners. Its benefits in terms of clinical efficacy and long-term health have made it an attractive choice for a wide range of congenital or acquired disorders such as hematological or solid tumors, autoimmune diseases or genetic diseases.

While Cell Therapies involve repairing or replacing damaged cells or tissues by transferring living cells as “living drugs” to the damaged tissue, Gene Therapies introduce, remove or modify the genetic material of the patient to regulate or alter the expression of target genes or influence regulatory activity at a genomic level.

Therapeutic Strategies in Cell and Gene Therapy

The choice of a therapeutic strategy to be adopted largely depends on the nature of the disorder to be treated (congenital or acquired), the available technologies, the immune status of the patient or the immunological risk of the individual solutions, and is intimately related with the kind of challenges in logistics and economies of scales expected for the treatment of the particular disease.

Although the unique combination of technologies and therapeutic strategies developed in the field of Cell and Gene Therapy greatly surpasses traditional Small or Large molecule approaches in terms of flexibility and efficiency, challenges in establishing complex yet robust manufacturing and logistics processes as well as navigating the regulatory landscape still remain to be solved by researchers and manufacturers on a case-by-case base and find limited consensus throughout the industry.

In the following paragraphs, we present the main therapeutic strategies employed in Cell and Gene Therapy and their implications.

Allogenic or autologous Cell Therapies?

Allogenic Cell Therapies

Allogenic strategies involve the isolation of cells from a single donor and their use for treatment of several patients usually after an expansion step. While this approach potentially poses immune-related risks in case donor and recipient are not HLA (human leukocyte antigen)-matched, it constitutes an attractive option for Cell Therapy developers, as it has the potential of better exploit economies of scale, lowering logistics and manufacturing costs.

Autologous Cell Therapies

Autologous strategies involve on the the other hand the isolation of cells from the patient to be treated and their re-infusion after expansion or modification into the same patient. While this approach poses only low immunogenicity or graft-versus-host disease risks, the difficult logistics related to the isolation, individual processing and re-infusion of the patient’s material, the variability of the starting material and the small production scale lead to higher development and commercialization costs.

As the previous considerations apply also to ATMPs such as CAR-T cell therapies, these novel strategies will here be discussed as similar to Cell Therapies.

CELL THERAPY STRATEGY

So, how to choose the optimal Cell Therapy strategy?

Asking yourself the following questions may help identifying it:

1. How easy it is to reach my patient or to move the patient to my facilities?

New technologies including last-mile drone delivery and automated bioreactors for Point-of-Care (POC) Cell Therapy Manufacturing made bridging the gap between bench to bedside easier and are currently contributing to the spreading of autologous therapies. They however bring with them a new level of complexity and costs that need to be factored in the economic evaluation of the therapeutic strategy, so if such therapies become unaffordable (eg in the case of high competitive markets or for rare diseases not well covered by health insurances or government plans) an allogenic strategy might be preferable.

2. How easy is to retrieve the starting material and optimize protocols?

In many cases, retrieval of healthy cells in sufficient quantities to develop and manufacture a cell therapy and the biological heterogeneity of the starting material pose a serious challenge to manufacturers. This is especially true when the amount of available tissue left is limited (eg after an accident or for vital organs). For developers facing such obstacles, allogenic therapies might constitute the optimal solution. A further advantage of starting with standardized material is the possibility to use it for training purposes, thus improving the flexibility of the organization. On this page you can find how BIOMEX can help you in the development of your Cell Therapy

3. How urgent is a treatment for my patient group?

The optimal strategy aims at balancing risks and benefits for the patient. If a life-saving treatment is urgently needed, immunological-related risks may become less relevant and an the availability of an “off-the-shelf” allogenic therapy may make the difference over the long production times of a personalized autologous cell therapy

4. How immunogenic is my Cell Therapy product?

While certain cell types (e.g. Mesenchymal Stem Cells, MSCs) present immunoregulatory or immunosuppressive activity, several new approaches aim at lowering the immunogenicity of the chosen strategy e.g. by knocking out proteins mediating immune responses in the chosen cell type or by choosing less immunogenic cell types altogether (e.g. choosing Natural Killer cells instead of T-Cells)

Viral or non-viral Gene Therapies?

Gene Therapies aim at altering the genetic material of individual cells by regulating, repairing, replacing, adding or deleting a genetic sequence of the cell to be treated in order to correct a genetic or epigenetic disorder.

The alteration of the genetic material can be performed by directly delivering the therapeutic agent to the target cells inside the patient’s body (in vivo) or by isolating the target cells from the donor or patient, genetically altering them and reintroducing into the patient (ex vivo). While in vivo strategies are usually performed by using viral vectors and their ability to enter cells and deliver genetic material (transduction), ex vivo strategies enjoy more flexibility in the choice of method and allow, in addition to viral vectors, for the manipulation of the genetic material with non-viral methods such as:

Electroporation
Nucleofection
Cationic

Liposomes
Polymers
Anorganic nanoparticles

Laser irradiation
Magnetoporation
Ultrasound

Viral Gene Therapies

Viral Gene Therapies employ either integrating viral vectors (like retroviruses and adeno-associated viruses – AAVs), which integrate their genetic material into the DNA of the infected cell; or non-integrating viral vectors (like adenoviruses), which introduce their genetic material into the cell nuclei, but do not integrate it into the cell’s chromosomal DNA, thus having only a transient effect. While the delivery of Viral Gene Therapies is a more straightforward therapeutic option which allows to exploit economies of scale thanks to the suitability of viral vectors for large-scale manufacturing, challenges such as toxicity at the therapeutic site or the induction of immune responses can represent major roadblocks in their clinical and pre-clinical development. If you are interested in de-risking your development of viral gene therapies, check how BIOMEX can help you with Immunogenicity-Immunotoxicity kits and our Immunogenicity Services

Non-Viral Gene Therapies

Although viral vector strategies are straightforward in their administration, development of standardized processes is quite costly and labor intensive, especially at clinical-scale manufacturing. Developers aiming at cheaper and shorter development cycles usually prefer adopting ex vivo non viral strategies. Developers aiming at scalable and standardized therapies for larger productions usually prefer adopting in vivo viral strategies. The main determinant for the choice of a therapy remains the accessibility of the tissue or cells to be genetically modified: in case they cannot be removed from their host without causing major damages, in vivo viral strategies are the only choice.

So, how to choose the optimal Gene Therapy strategy?

Asking yourself the following questions may help identifying it:

1. What is the incidence of the disorder I want to treat?

Ex vivo gene therapies require a larger logistic effort, as the patient’s material will need to reach the manufacturing facility and be re-administered after manipulation. Since Gene Therapies are usually targeted at chronic and genetic diseases (CAR-T and novel ATMPs for cancer treatment are better covered by the “Allogenic or autologous Cell Therapies?” section), this is generally not a problem, but as the manufacturing of ex vivo gene therapies is currently only poorly automated in the clinical practice, its scale up is difficult and costly and poorly suited for high incidence disorders. For high incidence disorders, in vivo (usually viral) strategies are preferable.

2. How easy is to retrieve the starting material and to optimize protocols?

3. How immunogenic or cytotoxic is my Gene Therapy product?

Significant progress has been made in reducing the immunogenicity of viral vectors, eg by producing Ancestor-AAVs strains lacking certain immunogenic surface proteins and partially solving the problem of pre-existent antibodies in patients. While it is not always possible to completely avoid immune reactions from viral vectors and these may be the only viable therapeutic option, it is possible to minimize the chance of unexpected reactions. If you are interested in de-risking your development of viral gene therapies, check how BIOMEX can help you with Immunogenicity-Immunotoxicity kits and our Immunogenicity Services.

4. How immunogenic is my Cell Therapy product?

Developing a Cell or Gene therapeutic strategy requires a careful consideration of the particularities of the disorder to be treated, the accessibility of the target tissue and the economic aspects related to the logistics and economies of scale of the development, manufacturing and ongoing personnel training.

Developing a Cell or Gene therapeutic strategy requires a careful consideration of the particularities of the disorder to be treated, the accessibility of the target tissue and the economic aspects related to the logistics and economies of scale of the development, manufacturing and ongoing personnel training.

During the preclinical and clinical development stages you will need a reliable and flexible partner able to react to changes in your demand and consistently delivering on your plans, enabling a smooth transition from development to commercialization.

If you are interested to know how BIOMEX can support in development, pipeline de-risking and manufacturing of your Cell and Gene Therapies, book a free consultation session!

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