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      15 October 2024

      Chimeric antigen receptor (CAR) T-cell therapy and phage display technology are two powerful tools for the treatment of cancer.1,2 As the industry improves and makes cancer treatment more accessible and effective, Medix Biochemica stands ready to adapt and support the changing needs of our customers.3

      Understanding CAR T-cell therapy

      What is CAR T-cell therapy?

      CAR T-cell therapy is a type of cancer immunotherapy used to treat certain blood cancers. Disease-fighting T-cells (white blood cells) are collected from the patient and genetically modified to become chimeric antigen receptor (CAR) T-cells which recognize the patient’s cancer cells. These specially modified CAR T-cells are grown and multiplied in a laboratory, and then infused back into the patient’s bloodstream to target and attack the cancer cells. CAR T-cell treatment is provided together with a chemotherapy regimen.1

      CAR T-cell Therapy - Diaclone

      Monoclonal antibodies are used to help identify antigens on the targeted cancer cells, enabling the CAR T-cells to more effectively recognize and bind to these antigens.3

       

      Current applications and successes of CAR T-cell cancer immunotherapy

      CAR T-cell therapy is currently used to treat certain cancers when other treatments aren’t effective or when the cancer returns, e.g. follicular lymphoma, high-grade B-cell lymphoma and multiple myeloma.1

      The success rate of CAR T-cell therapy for lasting remission is about 30% to 40%.4
      Challenges and limitations of CAR T-cell cancer therapy

      Accessibility is one of the biggest challenges of CAR T-cell therapy, with only 20% of the patients who need it having access to the treatment.5

      Factors affecting the accessibility of CAR T-cell therapy include the cost of the process and the time needed to manufacture the patient’s CAR T-cells. The cells currently take approximately three weeks to develop, which delays the patient’s start of treatment.5

      A number of adverse events can occur during CAR T-cell therapy, including CAR T-cell-associated toxicities like cytokine release syndrome, and this type of therapy also has limited efficacy against solid tumors5 (see targeting solid tumors below).

      The diagram below illustrates the different generations of CAR T-cells.6

      Different generations of CAR-T cells

      (a) Different generations of CAR-T cells. First-generation CAR-T cells include an intracellular domain. Second-generation CAR-T cells incorporate an additional co-stimulatory domain. Third-generation CAR-T cells include multiple co-stimulatory domains.

      (b) Structure of second-generation anti-CD19 CAR developed at the Immunology Department of Hospital Clínic de Barcelona.
            - Bartoló-Ibars A, 2021, Immunology Service—CDB, Hospital Clínic de Barcelona, Spain6

       

      The part of the CAR T-cell that gives it its specificity is a single-chain variable fragment (scFv)7 - the smallest unit of an antibody molecule that can bind to an antigen. One way to generate small antibody fragment is the use of phage display technology and ScFv libraries.

       

      Understanding phage display technology

      What is phage display technology?

      Phage display is a method of finding and selecting specific proteins or antibodies by displaying them on the surface of viruses called bacteriophages or phages.2 A phage library – a collection of phage particles expressing a wide variety of peptides – is used to select those that bind the desired target.8

      Did you know? Phages (or bacteriophages) are viruses that only infect and replicate in bacterial cells.9 They’re sometimes used as preservatives in food production and processing, to prevent contamination.10

      Phage display is used to identify proteins that can be used in therapeutic target identification, drug design and vaccine development.8

       

      Phage Display Biopanning - Diaclone

      The main stages of the phage display biopanning cycle.
      - Abd-Allah MI, 2021, Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt11

       

      How phage display is used in cancer treatment

      Phage display allows for the rapid development of scFvs against one target.7 

      The main advantage of using this technology is that candidates can be directly selected in their final desired format (namely scFv). Diaclone, a part of the Medix Biochemica Group, is able to develop scFvs that can be directly tested in CAR T construction.7

      “Due to their high specificity, manipulability, nontoxicity, and nanosize nature, phages are promising carriers in targeted therapy and cancer immunotherapy. This approach is particularly timely, as current challenges in cancer research include damage to healthy cells, inefficiency in targeting, obstruction by biological barriers, and drug resistance.” 
      – V. Ooi, 2024, Agricultural Biotechnology Laboratory, Baltimore, USA11

      Phages can be engineered to specifically target cancer cells, while leaving healthy cells alone. This can enhance the efficacy of cancer treatment therapy while reducing side effects.

      “Although the application of phages in cancer therapy is still at its early developmental phase, the potential advantages indicate that they may evolve into a crucial tool in the battle against cancer.” 
      – S. Islam, 2023, Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China12

       

      Emerging trends in CAR T-cell therapy

      Allogeneic products to improve accessibility 

      Because accessibility and manufacturing time are such major challenges, there has been a growing interest in the development of therapies where the T-cells are taken from healthy donor cells rather than from the patients themselves, providing an ‘off-the-shelf’ option that can be ready when a patient needs it.5 

      These donor-sourced products, known as allogeneic products, have several advantages:5

      • A high number of CAR T-cells can be produced from a single donor.
      • The products can be easily standardized and simplified based on donor selection and processing.
      • Allogeneic CAR T-cells may also allow for combinations directed against multiple targets.
      • Batches can be preserved so they are immediately available for treatment or redosing.
      • An industrialized manufacturing process could reduce costs.

      However, there are still many issues associated with allogeneic CAR T-cell therapy that need to be addressed, including cytokine release syndrome and graft-versus-host disease (GVHD).5

      Targeting solid tumors 

      As mentioned, CAR T-cell therapy of solid tumors has limited efficacy. Research into addressing this challenge is ongoing.

      Read more: Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR13

      Bispecific CAR T-cell therapy

      Another area of research is the use of CAR T treatment that can target multiple antigens simultaneously.

      Read more: Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial14

      Intracellular signal transduction optimization 

      Optimizing the communication between cells can lead to better efficacy and better outcomes.

      Read more: CAR-T cell therapy: current limitations and potential strategies15

      “Overall, studies suggest that proper CAR-T cell signaling may be best facilitated by linking the proximal intracellular domain to the corresponding transmembrane domain.” 
      – R Sterner, 2021, Blood Cancer Journal15

       

      Innovations in phage display technologies

      Integration with other biotechnologies 

      Phage display technology can be used together with other biotechnologies, such as bioinformatics16 and microfluidics.17 Bioinformatics involves using computer technology to collect, store, analyze and disseminate biological data.18 Microfluidics includes studying the behavior of fluids through micro-channels, and manufacturing microminiaturized devices containing tunnels that fluids flow through.19

      Read more: 

      Potential for personalized cancer vaccines

      Phage display vaccines can generate tailored immunogenic viral particles.

      Read more: Engineered phage-based cancer vaccines: current advances and future directions20

      In vivo phage display

      In vivo phage display selection is a promising tool for discovering cancer-targeting peptides with good stability and biodistribution. A phage library is injected directly into a living animal and the antibodies are allowed to bind directly to a specific organ or tissues.

      Read more: In vivo phage display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties21

       

      Phage display case study: Diaclone

      Diaclone, a part of the Medix Biochemica Group, specializes in advanced monoclonal antibody (mAb) development technologies for a wide range of service projects. This case study shows how phage display technology allows for mAb development that’s especially difficult to obtain with a classical fusion.22

      Antibody affinity modulation and optimization of activation signals for the development of a new generation of bispecific CAR T-cells:

      Diaclone is currently working in collaboration with an academic research team specializing in CAR T development. The aim of this project is to develop bi-specific CAR T against CD38 and BCMA. BCMA scFv candidates tested have been developed by an scFv phage display library at Diaclone. CD38 candidates have been reformatted as scFv from existing Diaclone full antibodies.7 

      In this work, Diaclone is the ScFv sequence provider. The various bispecific constructions have also been generated by Diaclone. The academic team is in charge of testing CAR T construction (transduction, activity, etc).7,22

      Read more: here22 

      The growth and advancements led by Diaclone, a part of the Medix Biochemica Group, continue even today.  October 2024 marked an exciting milestone for the team with the official launch of the EU-funded BioIMP project, aimed at advancing biomedicine development through improved manufacturing processes. Diaclone will contribute its recognized R&D expertise, focusing on bi-specific antibodies, a phage display naïve bank, and antibody affinity maturation.

      The launch, led by Marie-Guite Dufay, President of the Bourgogne-Franche-Comté Region, and Fanny Delettre, Director of EFS BFC, highlighted the project's importance for the future of healthcare and biotherapies, supported by the Region and the European Regional Development Fund.24

       

      Medix Biochemica at the forefront

      As a leader in the in vitro diagnostics raw materials industry, Medix Biochemica works to be your trusted partner to advance CAR T-cell therapy and phage display research – through a broad portfolio of existing products, custom development services and a team of the best minds in the industry ready to help at any stage of your project.3

      Contact our team of experts to discuss your requirements

      Get in Touch!

      References:

      1. What is CAR T-cell therapy? Cleveland Clinic. Accessed September 19, 2024. https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy.
      2. Bazan J, Całkosiński I, Gamian A. Phage display—a powerful technique for immunotherapy. Hum Vaccin Immunother. 2012;8(12):1817-1828. doi:10.4161/hv.21703.
      3. Expert opinion. Anthony Austin. Global Marketing Manager, Medix Biochemica. September 2024.
      4. Six years after CAR T-cell therapy for lymphoma, patient still cancer-free . UChicago Medicine. Accessed September 23, 2024. https://www.uchicagomedicine.org/forefront/cancer-articles/2021/december/a-walking-miracle-car-t-cell-therapy.
      5. CAR T-cells therapies: Opportunities and challenges. College of American Pathologists. Accessed September 23, 2024. https://www.cap.org/member-resources/articles/car-t-cells-therapies-opportunities-and-challenges.
      6. Bartoló-Ibars A, Uribe-Herranz M, Muñoz-Sánchez G, et al. CAR-T after stem cell transplantation in B-cell lymphoproliferative disorders: are they really autologous or allogeneic cell therapies? Cancers (Basel). 2021;13(18):4664. doi:10.3390/cancers13184664.
      7. Expert opinion. Pierre-Emmanuel Baurand. R&D Manager, Diaclone SAS. October 2024.
      8. Pande J, Szewczyk MM, Grover AK. Phage display: Concept, innovations, applications and future. Biotechnology Advances. 2010;28(6):849-858. doi:10.1016/j.biotechadv.2010.07.004.
      9. Kasman LM, Porter LD. Bacteriophages. In: StatPearls. StatPearls Publishing; 2024. Accessed September 25, 2024. http://www.ncbi.nlm.nih.gov/books/NBK493185/.
      10. Ranveer SA, Dasriya V, Ahmad MF, et al. Positive and negative aspects of bacteriophages and their immense role in the food chain. NPJ Sci Food. 2024;8(1):1. doi:10.1038/s41538-023-00245-8.
      11. Abd-Allah IM, El-Housseiny GS, Yahia IS, et al. Rekindling of a masterful precedent; bacteriophage: Reappraisal and future pursuits. Front Cell Infect Microbiol. 2021;11. doi:10.3389/fcimb.2021.635597.
      12. Ooi VY, Yeh TY. Recent advances and mechanisms of phage-based therapies in cancer treatment. Int. J. Mol. Sci.. 2024;25(18):9938. doi:10.3390/ijms25189938.
      13. Islam MS, Fan J, Pan F. The power of phages: Revolutionizing cancer treatment. Front Oncol. 2023;13. doi:10.3389/fonc.2023.1290296.
      14. Zhang AQ, Hostetler A, Chen LE, et al. Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR. Nat Biomed Eng. 2023;7(9):1113-1128. doi:10.1038/s41551-023-01048-8.
      15. Shi M, Wang J, Huang H, et al. Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: A phase I/II trial. Nat Commun. 2024;15(1):3371. doi:10.1038/s41467-024-47801-8.
      16. Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J. 2021;11(4):1-11. doi:10.1038/s41408-021-00459-7.
      17. Huang J, Ru B, Dai P. Bioinformatics resources and tools for phage display. Molecules. 2011;16(1):694-709. doi:10.3390/molecules16010694.
      18. Che YJ, Wu HW, Hung LY, et al. An integrated microfluidic system for screening of phage-displayed peptides specific to colon cancer cells and colon cancer stem cells. Biomicrofluidics. 2015;9(5):054121. doi:10.1063/1.4933067.
      19. Bioinformatics. National Human Genome Research Institute. Accessed September 25, 2024. https://www.genome.gov/genetics-glossary/Bioinformatics.
      20. Microfluidics: A general overview of microfluidics. Elveflow. Accessed September 25, 2024. https://www.elveflow.com/microfluidic-reviews/general-microfluidics/a-general-overview-of-microfluidics/.
      21. Ragothaman M, Yoo SY. Engineered phage-based cancer vaccines: Current advances and future directions. Vaccines (Basel). 2023;11(5):919. doi:10.3390/vaccines11050919.
      22. André AS, Moutinho I, Dias JNR, et al. In vivo phage display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties. Front Microbiol. 2022;13. doi:10.3389/fmicb.2022.962124.
      23. Farvaque-Josson P, Baurand PE, Sergent E, et al. Antibody affinity modulation and optimization of activation signals for the development of a new generation of bispecific CAR-T cells. Diaclone SAS - part of the Medix biochemica Group.
      24. BioIMP: Le projet bisontin qui va créer les biomédicaments du futur. Accessed 22 October 2024. https://www.bourgognefranchecomte.fr/bioimp-le-projet-bisontin-qui-va-creer-les-biomedicaments-du-futur