{"id":55934,"date":"2023-09-01T20:25:10","date_gmt":"2023-09-02T00:25:10","guid":{"rendered":"https:\/\/ifintechworld.com\/news\/cytomed-therapeutics-an-innovative-immunology-biotech-company-to-watch-nasdaqgdtc\/"},"modified":"2023-09-01T20:25:17","modified_gmt":"2023-09-02T00:25:17","slug":"cytomed-therapeutics-an-innovative-immunology-biotech-company-to-watch-nasdaqgdtc","status":"publish","type":"post","link":"https:\/\/ifintechworld.com\/?p=55934","title":{"rendered":"CytoMed Therapeutics: An Innovative Immunology Biotech Company To Watch (NASDAQ:GDTC)"},"content":{"rendered":"
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CytoMed Therapeutics (NASDAQ:GDTC<\/span>)<\/strong><\/h2>\n

CytoMed Therapeutics (GDCT, or the Company), a Singapore-based biotechnology company trading on the NASDAQ, is developing multiple gamma delta chimeric antigen receptor T-cell (\u201c\u03b3\u03b4 CAR-T\u201d) therapeutics for the treatment of cancer. The Company is one of many who are trying to exploit the body\u2019s immune system to help fight cancer and has licensed technology from A*STAR, a highly regarded research and development governmental organization in Singapore.<\/span><\/p>\n

Definitions and Abbreviations<\/strong><\/h2>\n

Autologous \u2013 Cell therapy where the patient\u2019s own cells are used.<\/p>\n

Allogeneic \u2013 Cell therapy where donor cells are used for multiple patients.<\/p>\n

Chimeric Antigen Receptor (\u201cCAR\u201d) – A special receptor created in the laboratory that is designed to bind to certain proteins on cancer cells. The CAR can then be added to T cells to make CAR-T cells.<\/p>\n

Human Leukocyte Antigen (\u201cHLA\u201d) – A type of molecule found on a cell surface that allows other cells to know if a given cell is part of the body, or a foreign substance. \u2013 Definition Source – <\/span>Wikipedia<\/p>\n

Induced Pluripotent Stem Cells (\u201ciPSC\u201d) \u2013 \u201cInduced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell.\u201d \u2013 Definition Source – Wikipedia<\/p>\n

Natual Killer Cells (\u201cNK cells\u201d) \u2013 \u201cA type of cytotoxic lymphocyte that is critical to the body\u2019s immune system. Its role is to provide rapid response to virus-infected or stressed cell, in the absence of HLA identification.\u201d \u2013 Definition Source – Wikipedia<\/p>\n

\u201cNon-Hodgkins Lymphoma (\u201cNHL\u201d) – A type of cancer that begins in your lymphatic system, which is part of the body’s germ-fighting immune system. In NHL, white blood cells called lymphocytes grow abnormally and can form growths (tumors) throughout the body\u201d \u2013 Definition Source \u2013 Bing Search<\/p>\n

CAR-T Cell Therapy Overview<\/strong><\/h2>\n

From a high level, autologous CAR-T cell therapy is relatively straight forward. T-cells are extracted from a patient\u2019s blood. The extracted T-cells are isolated and allowed to multiply. Once in sufficient quantities, an antigen receptor is added to the cells through gene editing, usually through an engineered virus. That chimeric antigen receptor (\u201cCAR\u201d) is designed to bind to a surface receptor on a cancer cell. The T-cell\u2019s normal job is to bind to target cell, start the process of destroying that cell, and recruit other immune system cells to assist in the destruction process. By adding a CAR to the surface of a T-cell, that CAR T-cell has a higher probability of attacking whatever cell becomes bound to that CAR. Thus, the CAR-T cell therapies are engineered to target and destroy cancer cells, and have become a very promising technology in the fight against cancer.<\/p>\n

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\"CAR-T<\/span>
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sec.gov\/Archives\/edgar\/data\/1873093\/000149315223012534\/form424b4.htm<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

Figure 1: General Autologous CAR-T cell Production Process<\/strong><\/p>\n

(Source: GDTC Form 20-F)<\/p>\n

Most all CAR-T programs have focused on the \u03b1\u03b2 T cell. For autologous therapies, only the \u03b1\u03b2 T cells exist in enough quantities to isolate, engineer and re-inject into the patient. Interestingly, in a post-hoc analysis of the cell types found in tumors of those patients who have gone into remission, \u03b3\u03b4 T cells are found in the highest relative proportion inside the tumors.<\/p>\n

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\"Gamma <\/picture>
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Nat Med. 2015 Aug; 21(8): 938\u2013945.<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

Figure 2: Prognostic Association of Various Relative Leukocytes Fractions Found in 9,000 Cancer Tumors<\/strong><\/p>\n

(Source: Nat Med. 2015 Aug; 21(8): 938\u2013945.)<\/p>\n

From a high level, \u03b3\u03b4 T cells seem to check a number of boxes that make them \u201cdrugable\u201d. A) The cells do not have HLA receptors which allows them to better avoid graft versus host issues. To make \u03b1\u03b2 T cells into an allogeneic product, HLA-binding receptors need to be blocked or removed, requiring multiple processing steps, prior to adding a CAR. B) Many subtypes of the \u03b3\u03b4 T cells naturally migrate into tissues, which help them target solid tumors. C) The cells naturally have surface receptors that only target cells that are either in stress or functioning improperly.<\/p>\n

Time will tell if human biology has some other way to recognize that an allogeneic \u03b3\u03b4 T cell is foreign and needs to be expelled. As a scientist and engineer in the life science space, I know that trying to manipulate biology can be a humbling experience. Just look at all the attempts to turn stem cells into therapies. We have survived as a species because it is hard for external microbes to manipulate our biology. Our bodies fight microscopic pathogens a million times a day. If it were easy to manipulate a cell into killing another cell, then we might not have evolved much past algae. The theory behind CAR-T cells is logical. Putting the theory into practice is very hard. The companies attempting these programs deserve a lot of respect.<\/p>\n

CytoMed Therapeutics – Pipeline<\/strong><\/h2>\n

The Company has three programs in pipeline, each of which could itself be a platform for multiple cancer indications.<\/p>\n

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\"Pipeline\"<\/span>
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sec.gov\/Archives\/edgar\/data\/1873093\/000149315223012534\/form424b4.htm<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

Figure 3: CytoMed Therapeutics Pipeline<\/strong><\/p>\n

(Source: GDTC Form 20-F)<\/p>\n

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  1. CTM-N2D: Allogeneic \u03b3\u03b4 T cells that have been edited to have an NK2GD receptor, which commonly found on NK cells. The NKG2D receptor recognizes induced-self proteins from MIC and RAET1\/ULBP families, which appear on the surface of stressed, malignant transformed, and infected cells. The therapy should be initiating its first in human studies in the back half of 2023.<\/li>\n<\/ol>\n

    There are over 20 clinical trials, mostly in China, that include the NKG2D receptor in an engineered cell therapy, and there are hundreds of journal articles on the receptor pathway. There is strong theoretical support for this CAR-T combination. Many other programs involving this receptor pathway should have data read out before CytoMed\u2019s trial and should be able to provide proof of concept guidance for multiple indications to CytoMed. Those data will enable the Company to focus future efforts on indications with higher than normal probability of success.<\/p>\n

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    \"CTM-N2D<\/span>
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    sec.gov\/Archives\/edgar\/data\/1873093\/000149315223012534\/form424b4.htm<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

    Figure 4: CTM-N2D Manufacturing Process<\/strong><\/p>\n

    (Source: GDTC Form 20-F)<\/p>\n

    When talking to the Company, one can get a better sense of their process. First, because the \u03b3\u03b4 T cells are only a small fraction of the cells isolated from blood, the Company runs the collected lymphocytes through a process to stimulate the expansion of the \u03b3\u03b4 T cells before they separate the \u03b3\u03b4 T cells from the other lymphocytes. Then the company stimulates the isolated \u03b3\u03b4 T cells to expand again to attain a large number of cells. Second, and unique to CytoMed, is their use of electroporation to incorporate the mRNA required to implant the CAR, instead of using a virus. The process of electroporation can cost less than using a virus when one considers the additional cost of maintaining the virus bank and of the additional in-process testing of the viral material.<\/p>\n

    CytoMed has expressed the goal of bringing down the cost of cancer therapy. I believe that they may be able to achieve a cost advantage with their processes. 400 ml of donor blood can generate at least 20 doses, assuming a high dose of 1 billion cells.<\/p>\n

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    1. iPSC-gdNKT: Allogeneic \u03b3\u03b4 T cells with NK cell properties. iPSC cells derived from \u03b3\u03b4 T-cells are pushed through an NK cell differentiation process. The net result is a hybrid \u03b3\u03b4 T-NK cell with surface receptors that bind to multiple surface receptors common on cancerous cells.<\/li>\n<\/ol>\n

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      \"iPSC<\/span>
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      sec.gov\/Archives\/edgar\/data\/1873093\/000149315223012534\/form424b4.htm<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

      Figure 5: iPSC-gdNKT Manufacturing Process<\/strong><\/p>\n

      (Source: GDTC Form 20-F)<\/p>\n

      In my opinion, of all of CytoMed\u2019s programs, this product platform has the most potential to become a pipeline in a product. By combining the properties of \u03b3\u03b4 T cells and NK cells, there is a strong potential to bind to multiple cellular abnormalities that could elude normal T cells or NK cells. This program is very early, and is not expected to be in patients for a few years.<\/p>\n

      One could imagine that, once they have validated all of the steps to consistently generate these cells, that the Company could then add a CAR to these cells at the iPSC stage, potentially creating a very potent, highly targeted CAR-T\/NK cell. That would be a very interesting platform.<\/p>\n

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      1. CTM-GDT: Allogeneic \u03b3\u03b4 T cells with no modifications. These cells will be extracted from healthy donors and expanded to provide a consistent source of off-the-shelf \u03b3\u03b4 T cells to patients.<\/li>\n<\/ol>\n

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        \"CTM-GDT<\/span>
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        sec.gov\/Archives\/edgar\/data\/1873093\/000149315223012534\/form424b4.htm<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

        Figure 6: CTM-GDT Manufacturing Process<\/strong><\/p>\n

        (Source: GDTC Form 20-F)<\/p>\n

        CytoMed\u2019s CTM-GDT program is a simple cell replacement therapy. Because the \u03b3\u03b4 T cells do not use HLA in their interaction with other cells, they have a lower probability of creating an immune response when transplanted into a patient than do \u03b1\u03b2 T cells, the predominant form of T cells. \u03b1\u03b2 T cells rely on HLA interactions, which is why the initial CAR-T cell therapies are autologous. The CTM-GDT product does not have any CAR engineering, and therefore relies on the natural anti-cancer properties of the \u03b3\u03b4 T cell. \u03b3\u03b4 T cells, which represent a very small fraction of total T cells, recognize markers of cellular stress independent of cell source, be it a bacteria or a patient\u2019s cancer cell. \u03b3\u03b4 T cells also can accumulate inside tissues at the location of solid tumors. As a product, CTM-GDT could act as an immune booster, equivalent to putting more police on the street to look for bad actors.<\/p>\n

        Through a compassionate use program, some patients have already received CTM-GDT. At least 9 patients who had very late-stage cancer received serial infusions of \u03b3\u03b4 T cells harvested and expanded from healthy donors. Multiple patients had a partial response, and the company believes a few patients may still be alive 2 years after receiving their last dose. The Company has not had the bandwidth to track down these patients and review their medical history from the end of dosing (last dose of first group was in late 2021). The dose was likely 10-50x lower than what would be the high dose in their next clinical trial, so the data may or may be useful. While management has not published the results from the program, the fact that they are pursuing this program of unmodified \u03b3\u03b4 T cells suggests that they have seen enough efficacy to make it worth the expense, and enough safety for the regulatory authorities to allow the program to continue.<\/p>\n

        If proven safe, I believe this kind of therapy could eventually be seen as an immune booster that could be given to any cancer patient early in the diagnosis process, akin to the Multikine\u00ae therapy developed by CEL-SCI (CVM). The Phase 3 for Multikine\u00ae was arduously long because of the type of cancer pursued. CtyoMed could target more aggressive cancers and have a shorter, cheaper trial. Note: CytoMed has made no mention of pursuing this pathway \u2013 this is purely conjecture on my part.<\/p>\n

        Platform Companies with Competitive Programs<\/strong><\/h2>\n

        There are many companies developing CAR-T cell therapeutics. A majority of them, including the thought-leader in the allogeneic space, Allogene Therapeutics (ALLO), focus on the modification of \u03b1\u03b2 T cells to both reduce graft versus host risk and better target certain cancers. Others in the space are working on NK cell products. CytoMed has put its scientific eggs into the \u03b3\u03b4 T cell basket, with their most interesting program being a combination of \u03b3\u03b4 T cells and NK cell properties. The companies below also have clinical stage programs using \u03b3\u03b4 T cells. There are likely many more that have earlier stage programs.<\/p>\n

        Adicet Bio (ACET – $77M mkt cap w\/ ($100M) EV)<\/strong> – ADI-001 is an investigational allogeneic gamma delta CAR T cell therapy being developed as a potential treatment for relapsed or refractory B-cell NHL. ADI-001 targets malignant B-cells via an anti-CD20 CAR and via the gamma delta innate and T cell endogenous cytotoxicity receptors.<\/p>\n

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        \"Production<\/span>
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        Adicet Bio – Corp Presentation<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

        Figure 7: Adicet Bio\u2019s \u03b3\u03b4 CAR T Cell production process<\/strong><\/p>\n

        (Source: Adicet Bio)<\/p>\n

        Century Therapeutics (IPSC – $152M mkt cap w\/ $37M EV)<\/strong> \u2013 Most of Century\u2019s pipeline consist of allogeneic iPSC-derived NK and T cell products. IPSC creates a cell bank of induced pluripotent stem cells from a healthy donor, and then uses gene editing to remove receptors that might cause an immune reaction when administered to patients. They have one \u03b3\u03b4 T cell product, CNTY-107, which is a \u03b3\u03b4 iT product candidate for the treatment of solid tumors expressing Nectin-4.<\/p>\n

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        \"Process\" <\/picture>
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        Century Therapeutics – Corp Pres<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

        Figure 8: Century Therapeutics\u2019 process to remove receptors that might cause host rejection<\/strong><\/p>\n

        (Source: Century Therapeutics)<\/p>\n

        Gadeta NV<\/strong> (private)<\/strong>\u2013 GDT002 is an allogeneic-like therapy that harvests a patients \u03b1\u03b2 T cell, then adds specific \u03b3\u03b4 T cell receptors to the \u03b1\u03b2 T cell. When returned to the patient, the new cells have the proliferation tendency of the an \u03b1\u03b2 T cell and the broad tumor fighting capability of an specific \u03b3\u03b4 T cell.<\/p>\n

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        \"Gadeta <\/picture>
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        Gadeta Thera – Corp Pres<\/span><\/p>\n<\/figcaption><\/figure>\n<\/p>\n

        Figure 9: Gedeta\u2019s GDT002 manufacturing process<\/strong><\/p>\n

        (Source: Gadeta NV)<\/p>\n

        Valuation<\/strong><\/h2>\n

        It is too early in development to provide a rigorous valuation of CtyoMed. None of the Company\u2019s programs have been dosed in patients in a clinical trial. Initial approval to dose patients has been given, which suggests that the program has passed regulatory scrutiny of their toxicology work and of their manufacturing processes. However, until the program safely doses patients, the Company\u2019s technology is unproven. That will change soon, as the Company\u2019s CTM-2MD program is scheduled to begin its first clinical trial by the end of 2023. Once the company completes the dosing of a clinical trial, many of the biggest risks will have been mitigated.<\/p>\n