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IMMUNOTHERAPY WORKFLOW
Immunotherapy involves understanding and harnessing the relationship between the immune system and diseases.
Based on this analysis, immunotherapy is a type of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases. Development of immunologic-based biopharmaceutical products have strikingly increased in recent years and have made evident contributions to human health.
immunotherapy workflow

Cancer is one of the biggest challenges we face :

13M PEOPLE will die from cancer in 2035 (WHO), 40% OF PEOPLE will get cancer in their lifetimes (ACS), 1.2T DOLLARS and no sense - The cost of cancer globally (WHO).
Antibodies are the leading entity in immunotherapy, while chimeric antigen receptor T cells therapies are the advent of a novel strategy in this area. There are many potential immunotherapeutic approaches, including cell-based strategies such as adoptive cell transfer, receptor pathway-based strategies such as checkpoint inhibition, and agent-based approaches such as antibody therapy.

Genetic engineering can be incorporated into all of these approaches. Gene editing can be used to modulate receptor expression levels, induce the production of certain molecules, change cellular phenotypes, or alter the overall intensity of the immune response.

Today, cell therapies are constantly evolving and improving and providing new options to cancer patients. Cell therapies are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials. Adoptive cell therapy (ACT), also known as cellular immunotherapy, is a form of treatment that uses the cells of our immune system to eliminate cancer. Some of these approaches involve directly isolating our own immune cells and simply expanding their numbers, whereas others involve genetically engineering our immune cells (via gene therapy) to enhance their cancer-fighting capabilities. 

The cells used can come from 2 different sources depending on the process followed. In autologous transplants, they come from the same person who will get the transplant, so the patient is their own donor. Conversely, allogeneic transplant cells come from a person other than the patient, be it a related or unrelated donor.

Our immune system is capable of recognizing and eliminating cells that have become infected or damaged as well as those that have become cancerous.
In the case of cancer, immune cells known as killer T cells are particularly powerful against cancer, due to their ability to bind to markers known as antigens on the surface of cancer cells. Cellular immunotherapies take advantage of this natural ability and can be deployed in different ways:

Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy, Natural Killer (NK) Cell Therapy.

By combining the tools of synthetic biology such as CARs and CRISPR/Cas9 4, we have an unprecedented opportunity to optimally program T cells and improve adoptive immunotherapy for most, if not all future patients.

The somatic mutations acquired by cancer cells can be recognised as ‘non-self’ by the immune system and are capable of inducing an immune response that can selectively target and remove tumour cells. There are a number of steps required in order for the peptides to be displayed to the immune system and each of these processes has optimal conditions under which they occur. Therefore, despite there being a large number of potential neoantigens5  in some cancers with high mutation burden, only a fraction are able to ultimately mount an immune response. With the improvement in molecular and in silico capabilities in recent years, the number of identified immunogenic neoantigens has substantially increased. With a greater number of verified neoantigens, the better the ability of trained in silico prediction tools to reliably identify those that may have clinical utility.

Analis provides unmatched expertise to support the development of cancer immune therapies, including: Adoptive Cell Therapies (ACT), CAR T-Cell Therapies1, Immune Checkpoint Inhibitor2, Gene Therapies3Vaccines. We are keen to advance the next generation of cell therapies, through exploring how to robustly validate assays and advance the characterization of cell immunotherapy analytics to ensure safe, effective and quality cell therapy products.

Introduction videos

Immunotherapy Introduction and Overview
Discussion around the basics of immunotherapy and related agents and techniques that are commonly used

CAR-T Cell Therapy: Introduction and Overview
Featured video on the introduction of CAR-T cell therapy as related to immunotherapy

Relevant webinars

Is Immunotherapy Living up to its Promise?
Watch this webinar on the advancements and performance of immunotherapy, presented by Jill O'Donnell-Tormey and Alex Y. Huang

1  Adoptive cell therapy using Chimeric Antigen Receptor T cells (CAR-T cells) is a promising cancer immunotherapy strategy and has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells (either a patient’s own or a donor’s) to express a chimeric antigen that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. CAR‐T therapies are considered advanced therapy medicinal products (ATMPs) in Europe, and more specifically gene therapy medicinal products (GTMPs).

2  Drugs called Immune Checkpoint Inhibitors work by releasing a natural brake on your immune system so that immune cells called T cells recognize and attack tumors.
This therapy is sometimes called immune checkpoint blockade because the molecule that acts as a brake on immune cells — the checkpoint — is blocked by the drug. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.

3  Human Gene Therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. Gene therapy is a technique that modifies a person’s genes to treat or cure disease.
Gene therapies can work by several mechanisms:
  • Replacing a disease-causing gene with a healthy copy of the gene
  • Inactivating a disease-causing gene that is not functioning properly
  • Introducing a new or modified gene into the body to help treat a disease
Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases. There are a variety of types of gene therapy products, including:
  • Plasmid DNA: Circular DNA molecules can be genetically engineered to carry therapeutic genes into human cells.
  • Viral vectors: Viruses have a natural ability to deliver genetic material into cells, and therefore some gene therapy products are derived from viruses. Once viruses have been modified to remove their ability to cause infectious disease, these modified viruses can be used as vectors (vehicles) to carry therapeutic genes into human cells.
  • Bacterial vectors: Bacteria can be modified to prevent them from causing infectious disease and then used as vectors (vehicles) to carry therapeutic genes into human tissues.
  • Human gene editing technology: The goals of gene editing are to disrupt harmful genes or to repair mutated genes.
  • Patient-derived cellular gene therapy products: Cells are removed from the patient, genetically modified (often using a viral vector) and then returned to the patient.
4 The clustered regulatory interspaced short palindromic repeat/CRISPR-associated protein 9 (CRISPR/Cas9) technology holds immense promise for advancing the field owing to its flexibility, simplicity, high efficiency and multiplexing in precise genome editing. CRISPR systems cleave double stranded DNA, triggering a host repair mechanism which can inactivate the gene by introducing insertion/deletion mutations at the cleavage site. However, the true utility of CRISPR is that this cleavage can be directed using guide RNAs, allowing scientists to inactivate specific genes of interest
Despite the success of CAR-T cell therapies, a number of patients are unable to receive this therapy due to inadequate T cell numbers or rapid disease progression. Furthermore, lack of response to CAR-T cell treatment is due in some cases to intrinsic autologous T cell defects and/or the inability of these cells to function optimally in a strongly immunosuppressive tumor microenvironment. Recent efforts to overcome these limitations using CRISPR/Cas9 technology have been described, with the goal of enhancing potency and increasing the availability of CAR-based therapies. By combining the tools of synthetic biology such as CARs and CRISPR/Cas9, there is an unprecedented opportunity to optimally program T cells and improve adoptive immunotherapy for most, if not all future patients.
For more information on how CRISPR can be used in immunotherapy, please watch the short video in STEP 2. VECTOR DESIGN & PRODUCTION.

 5  A Neoantigen is a new protein that forms on cancer cells when certain mutations occur in tumor DNA, it may play an important role in helping the body make an immune response against cancer cells.

Start the workflow here.

Sources :

 Waldman, A.D., Fritz, J.M. & Lenardo, M.J. (2020). A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20, 651–668 (2020). https://doi.org/10.1038/s41577-020-0306-5
Salas-Mckee, J., Kong, W., Gladney, W. L., Jadlowsky, J. K., Plesa, G., Davis, M. M., & Fraietta, J. A. (2019). CRISPR/Cas9-based genome editing in the era of CAR T cell immunotherapy. Human vaccines & immunotherapeutics, 15(5), 1126–1132. https://doi.org/10.1080/21645515.2019.1571893
Hutchison, S., & Pritchard, A. L. (2018). Identifying neoantigens for use in immunotherapy. Mammalian genome : official journal of the International Mammalian Genome Society, 29(11-12), 714–730. https://doi.org/10.1007/s00335-018-9771-6
Immunotherapy Research and Information - Beckman Coulter

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