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The three existing general cell and gene therapy strategies

1. Cell therapies repair or replace damaged cells or tissue and involve the injection of intact, living cells into a patient. These cells are either derived from the patient (autologous cell therapy) or a donor (allogeneic cell therapy). Cell therapies can be categorized as those utilizing hematopoietic/stem cell approaches or immune cell approaches



2. Gene therapy involves introducing, removing, or changing genetic material to alter how a protein or group of proteins is produced in a cell, to alleviate or cure a disease. Gene therapies show great promise with the advancement of genome editing techniques. Currently the FDA has approved gene therapies for an eye disorder called Leber congenital amaurosis and a muscle disorder called spinal muscular atrophy. Gene therapy is typically performed in vivo but there are ex vivo approaches as well. One has the option to choose between viral and non-viral gene therapy. In vivo gene therapy using adeno-associated viruses (AAV) is one of the most common applications.

3. Cell and gene therapies are in some applications combined using ex vivo genetically modified cells as therapeutic agent (cell-based gene therapy) such as ex vivo chimeric antigen receptor (CAR)-T cell therapy. Cell and gene therapy technologies can be autologous or allogeneic. Autologous transplantation is patient specific, whereas allogeneic transplantation extracts cells from a universal donor before cell expansion and delivery into multiple patients.


Each approach has advantages and challenges.

Cell & Gene Therapy Comparisons

Comparison of autologous and allogeneic transplantation
 

Autologous transplantation is patient specific, whereas allogeneic transplantation extracts cells from a universal donor before cell expansion and delivery into multiple patients. Each approach has advantages and challenges.

Some examples of autologous cell therapies are the use of CD19-directed genetically modified autologous T cell immunotherapy for the treatment of relapsed or refractory large B-cell lymphoma and Autologous cellular immunotherapy consisting of CD54+ cells activated with PAP-GM-CSF for the treatment of metastatic castration-resistant prostate cancer.

Allogeneic cell therapy examples include the use of ready-to-use cellular scaffold consisting of human keratinocytes, fibroblasts to create vascular wound bed in the treatment of mucogingival conditions.

allegineic
Autologous Allogeneic
Advantages

Patient-specific 

No rejection by the immune system 

No risk for graft-vs-host disease 

Repeated doses possible 

Larger-scale manufacturing possible (industrial scale, more cost-effective) 

More reproducible manufacturing due to less heterogeneity of donor material 

Banking possible (immediate availability) 

Donor can be screened for desirable characteristics 

Enables treatment of multiple patients

Challenges

High costs for manufacturing and quality testing because of small lot size 

Starting material variability (donor variability) 

Re-dosing limited because of cell numbers 

Patient cells may be more fragile than from healthy donors

Minimizing risk for graft-vs-host disease required additional gene editing step (cost increase) 

Risk of rapid rejection as cells are still recognized as foreign cells (short persistence, no multiple dosage) 

Limited expansion potential of T cells before reaching senescence (short persistence) 

Re-dosing limited by risk of alloimmunization

Comparison of viral versus non-viral approaches
 

For in vivo gene therapy, the current standard is transferring a therapeutic gene into the patient using a virus. In ex vivo therapy, a gene modification is introduced into cells isolated from a patient by viral or non-viral methods and then re-injected. Again, each version has advantages and challenges.  

Viral Transduction  Non-viral transfection
 gammaRV  LV  AV  AAV  Transposon  CRISPR, TALEN, ZFN  mRNA
Use mode  In vivo, ex vivo   Ex vivo
Efficiency  Moderate  Moderate  High  Moderate  Moderate  Moderate  High
Integration into genome   Yes  Yes  No  Yes  Yes Yes  No
Expression  Stable  Stable  Transient

 Stable

 Site-specific 

 Stable

 Stable

 Site-specific 

 Transient
Co-delivery of multiple cargo   Yes (polycistronic vectors)  Yes (polycistronic vectors or co-transfection
Insert size  ≤ 10 kb  ≤ 9 kb

 8-12 kb

 up to 36 kb with helper 

 ≤ 5 kb  Variable
Immunogenicity  Moderate  Moderate  High  Low  Low Low  Low
Risk of insertional mutagenesis  Yes  Yes  No  Low  Yes  Yes  No
Multiple dose potential  Low  Low  Low  Low *  Moderate Moderate High 
Suited for dividing and non-dividing cells  Dividing only  Non-dividing and dividing   Non-dividing (dependening on transfer method) and dividing
Biosafety level  BSL-2  BSL-2+  BSL-2  BSL-1 or BSL2 **  BSL-1

* Multiple dosing may cause immune response
** Depending on presence of helper virus and/or oncogenicity of insert

Related Resources

Digitalizing cell and gene manufacturing

Case study

Case study examining how MES Solutions improve operational efficiency and save costs.  MES solutions can remove paper from the manufacturing floor— while boosting operational efficiency and saving costs.

Cell therapies – Bringing it all together

Digital Roundtable Discussion

Join leading cell therapy thought leaders as they share their insights and lessons learned on advancing therapies from bench to bedside, the challenges they face, and where in their view the fast-evolving cell therapy field is heading.

Presented by CAR-TCR Digital Week

Overcoming Challenges in Cell and Gene Therapy

eBook

Download this eBook and discover why a clear vision of the end goal is important to accelerate cell and gene therapy development.


 

Industry Challenge
Scale-up and GMP Compliance for Cell and Gene Therapy

Cell and gene therapies are transforming how patients with cancer and genetic diseases are treated. Although the therapeutic opportunities for patients are promising, the stakes for drug developers are high. Companies wishing to scale up the manufacture of cell and gene therapy from translational research to the clinical trials phase must address complex challenges. For example, scaling up production under GMP conditions or dealing with regulatory bodies. Additionally, smaller operations may experience further inefficiencies and costs owing to paperwork-heavy compliance processes.


Traditionally GMP solutions for cell and gene therapy are not implemented until later in the process, however the use of research grade materials in the transitional phase may lead to invalidated experiments, new filings being needed, and more back and forth with regulatory agencies to defend decisions made earlier on, right at the finish line. Collaborating with a strong and experienced partner can help you succeed on this path.
 

TheraPEAK®  Products

Products and Services Supporting Research to Manufacturing

Our portfolio of research and manufacturing media, non-viral transfection technologies and primary cell systems, supports you through every step of the cell and gene therapy process. Together with our Cell and Gene Therapy Development and Manufacturing Services, we can help you successfully navigate the path from early discovery to commercialization, and make your journey as easy as possible.


Explore our portfolio

Research grade cells

Research-grade cells

Our primary human immune cells offering.

RUO-grade media

RUO-grade media

Cell-type specific serum-free media.
 

RUO-grade media

GMP-grade media, accessories, and reagents

GMP-grade transfection

GMP-grade transfection

For large-scale electroporation.
 


BET

Endotoxin testing

Supporting mandatory safety testing required by EP and USP.

Digitalization / MES

Digitalization / MES 

Enabeling more efficient, effective and flexible data capture. 

Manufacturing platform

Manufacturing platform

Versatile and scalable platform for cell therapy manufacturing.

Manufacturing services

Manufacturing services

CDMO partner for CGT development and manufacturing needs.

References

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Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf' allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020 Mar;19(3):185-199

Ghosh S, Brown AM, Jenkins C, Campbell K. Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges. Journal of ABSA International 2020, Vol. 25(1) 7-18

Grens K. The Next Frontier of CAR T-Cell Therapy: Solid Tumors. The Scientist. 2019 Apr

Kim B J and Waheed N K. Gene Therapy for Ocular Diseases. Genetic Diseases of the Eye (2nd edition), edited by Elias I Traboulsi, 2012

Lundstrom K. Viral Vectors in Gene Therapy. Diseases, 2018, Jun; 6(2):42

Mahajan R. Onasemnogene Abeparvovec for Spinal Muscular Atrophy: The Costlier Drug Ever. Int J Appl Basic Med Res. 2019 Jul-Sep;9(3):127-128

Marintcheva B. Virus-Based Therapeutic Approaches. Harnessing the Power of Viruses. 2018, 9.3.1.

Ramamoorth M and Narvekar A. Non Viral Vectors in Gene Therapy: An Overview. Journal of Clinical and Diagnostic Research, 2015 Jan; 9(1): GE01–GE06

Samulski R J and Muzyczka N. AAV-Mediated Gene Therapy for Research and Therapeutic Purposes. N. Annual Review of Virology. 2014 Nov;1(1):427-51.

StrataGraft® Skin Tissue in the Promotion of Autologous Skin Regeneration of Complex Skin Defects Due to Thermal Burns That Contain Intact Dermal Elements ClinicalTrials.gov ID NCT03005106

Wei XX, Fong L, Small EJ. Prostate Cancer Immunotherapy with Sipuleucel-T: Current Standards and Future Directions. Expert Rev Vaccines. 2015;14(12):1529-41