CHIMERIC ANTIGEN RECEPTOR & HYPERBARIC OXYGEN THERAPY

 

Hyperbaric Oxygen Therapy is a form of "Chimeric Antigen Receptor Therapy" in that HBOT modulates "gene expressions".

 * HBOT impacts cytokine gene expressions and may work by ‘re-setting‘ or ‘re-booting’ the immune system. HBOT reduces pro-inflammatory cytokine gene expressions including chronic inflammatory cascades, which in turn may lead to improvement in damaged organs and tissues.

 

Hemopoietic stem cells work best if chronic inflammation can be "switched off".

 ** Hyperbaric Oxygen mobilises and elevates both the production and circulation of pluripotent bone marrow stem cells which activates other circulating stem cells unique to the body speeding up healing and regeneration (Thoms 2005).

Chimeric Antigen Receptor - next generation, is referred to as TRUCKs - T cell Redirected for Universal Cytokine-mediated Killing in cancer immunotherapy and how to "best augment the antitumor potency using cytokines to safely improve treatment outcomes in patients with advanced blood or solid tumors"

Fueling Cancer Immunotherapy With Common Gamma Chain Cytokines. Front. Immunol., 20 February 2019 | https://doi.org/10.3389/fimmu.2019.00263

Herald Sun Newspaper, 3 August 2019

https://en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell

Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy.[1]

Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein. The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor.

CAR-T cell therapy uses T cells engineered with CARs for cancer therapy.

The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them. Scientists harvest T cells from people, genetically alter them, then infuse the resulting CAR-T cells into patients to attack their tumors.[2] 

CAR-T cells can be either derived from T cells in a patient's own blood (autologous) or derived from the T cells of another healthy donor (allogeneic). Once isolated from a person, these T cells are genetically engineered to express a specific CAR, which programs them to target an antigen that is present on the surface of tumors. For safety, CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells.[3]

After CAR-T cells are infused into a patient, they act as a "living drug" against cancer cells.[4] When they come in contact with their targeted antigen on a cell, CAR-T cells bind to it and become activated, then proceed to proliferate and become cytotoxic.[5] 

 

 * CAR-T cells destroy cells through several mechanisms, including extensive stimulated cell proliferation, increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the increased secretion of factors that can affect other cells such as cytokinesinterleukins and growth factors.[6]

 ** The patient undergoes lymphodepletion chemotherapy prior to the introduction of the engineered CAR-T cells.[10] The depletion of the number of circulating leukocytes in the patient upregulates the number of cytokines that are produced and reduces competition for resources, which helps to promote the expansion of the engineered CAR-T cells.[11]

T cells are genetically engineered to express chimeric antigen receptors specifically directed toward antigens on a patient's tumor cells, then infused into the patient where they attack and kill the cancer cells.[12] Adoptive transfer of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target virtually any tumor associated antigen. There is great potential for this approach to improve patient-specific cancer therapy in a profound way.

 

Early CAR-T cell research has focused on blood cancers. The first approved treatments use CARs that target the antigen CD19 (gene), present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).

There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including CD30 (TNFRSF8, is a cell membrane protein of the tumor necrosis factor receptor family and tumor marker.) in refractory Hodgkin's lymphoma; CD33 (It is usually considered myeloid-specific, but it can also be found on some lymphoid cells).

Other CAR's include: CD123 (interleukin-3 receptor (CD123) is a molecule found on cells which helps transmit the signal of interleukin-3.

 * CD123 receptor is found on pluripotent progenitor cells and promotes proliferation and differentiation within the hematopoietic cell lines.

 ** FLT3 in acute myeloid leukemia (AML); and BCMA (B-cell maturation antigen (BCMA or BCM), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein that in humans is encoded by the TNFRSF17 gene) in multiple myeloma.[13]

Solid tumors have presented a more difficult target.[14] 

Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues. CAR-T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumor microenvironment suppresses T cell activity.[13]

 

Solid Tumors are "hypoxic"  (Oxygen deprived) and rationale for Hyperbaric Oxygen Therapy.

 * 'Hyperbaric Oxygen Therapy (HBOT) may increase the amount of oxygen in cancer cells, which may make them easier to kill with radiation therapy and chemotherapy. HBOT is a type of radiosensitizing agent and a type of chemosensitizing agent.

 ** HBOT assists immune responses to chemotherapy reducing immunosuppression and neutropenia'.

 www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45218

The diagram above represents the process of chimeric antigen receptor T-cell therapy (CAR), this is a method of immunotherapy, which is a growing practice in the treatment of cancer. The final result should be a production of equipped T-cells that can recognize and fight the infected cancer cells in the body.

  1. T-cells (represented by objects labeled as ’t’) are removed from the patient's blood.

  2. Then in a lab setting the gene that encodes for the specific antigen receptors are incorporated into the T-cells.

  3. Thus producing the CAR receptors (labeled as c) on the surface of the cells.

  4. The newly modified T-cells are then further harvested and grown in the lab.

  5. After a certain time period, the engineered T-cells are infused back into the patient.

IL13appt.PNG
IL13bppt.PNG

Mol Ther. 2018 Jan 3;26(1):31-44. doi: 10.1016/j.ymthe.2017.10.002. Epub 2017 Oct 5.

Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma.

T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8+ T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors.

Hyperbaric Oxygenation of Hypoxic Glioblastoma Multiforme Cells Potentiates the Killing Effect of an Interleukin-13-Based Cytotoxin

 - IL13 has anti-tumour effects and when combined with HBO enhances the killing effects of Glioblastoma and other cancers. 

 - Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to human glioblastoma (GBM) cells.

Bone Marrow Transplantation volume 54, pages933–942 (2019) 

General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE)

Autoimmune diseases (ADs) are a broad group of illnesses where the body’s immune system reacts against its own tissues and organs. The immune attack is followed by chronic inflammation and abnormal healing, which may be associated with permanent organ damage, disability and poor quality of life. In some cases, severe ADs may shorten life expectancy or even be immediately life-threatening.

The types of organs affected vary between ADs. For example, systemic sclerosis, lupus, vasculitis and other connective tissue diseases affect many organs, typically causing inflammation and scarring of the skin, heart, lungs, kidneys and other organs. Multiple sclerosis (MS) affects the brain and spinal cord, whereas Crohn’s disease affects the gut.

Treatment with immunosuppressant drugs, including disease modifying treatments (DMTs), may be successful in controlling the AD, but there is an increased susceptibility to infection and organ damage, which add to the problems of living with an AD.

Some patients have very aggressive forms of autoimmune disease which are poorly controlled by standard therapies. In some of these severely affected patients, there may be benefit in considering bone marrow transplantation (BMT), or, as it is now more commonly known, haematopoietic stem cell transplantation (HSCT) [1,2,3].

  • Haematopoietic stem cell transplantation (HSCT) has been used in patients with severe autoimmune and inflammatory diseases whose response to standard treatment options has been limited and associated with a poor long-term prognosis in terms of survival and/or disability. The vast majority of patients have received autologous HSCT, with the use of allogeneic HSCT being rare and mainly in paediatric patients.

  • Although a wide range of autoimmune diseases have been treated, the evidence base is greatest for the use of autologous HSCT in relapsing remitting MS, diffuse systemic sclerosis and Crohn’s disease.

  • HSCT may work by ‘re-setting‘ or ‘re-booting’ the immune system, which in turn may lead to improvement in damaged organs and tissues. HSCT works best if active inflammation can be switched off, but the effect of HSCT may be limited (or no benefit at all) if there is no active inflammation. There is no proof that the blood stem cells can directly rebuild specialised tissues, although the absence of inflammation may enable some damaged tissues and organs to heal over time

  • Compared with most standard treatments, HSCT is associated with greater short-term risks, including a risk of treatment related mortality (TRM), and long-term complications (so called ‘late effects’) due to the intensity of the treatment. The risk of complications is higher with autologous HSCT in some types of diseases and in allogeneic HSCT. Risks increase with age, more advanced disease and the presence of other conditions which affect patients’ fitness. Decisions should be individualised for each patient.

Fueling Cancer Immunotherapy With Common Gamma Chain Cytokines. Front. Immunol., 20 February 2019 | https://doi.org/10.3389/fimmu.2019.00263

Use of γc cytokines for ex vivo T cell expansion generates T cells with variable memory phenotypes. γc cytokines promote different biological programs that influence the differentiation of T cells. While IL-2 promotes robust proliferation it also promotes terminal effector differentiation. IL-7 and IL-15 maintain the homeostasis and survival of memory T cells and treatment ex vivo promotes a Tscm/Tcm phenotype. IL-21 slows T cell expansion but prevents differentiation and maintains a naïve-like T cell phenotype. With respect to antitumor immunity, less differentiated cell products are more therapeutic leading to the understanding that IL-2 is not the best option for ex vivo expansion.