Immunotherapeutic Niches, Competition and Collaboration. Part II: The Cellular Approach
This five-part series covers DCVax and other immunotherapeutic approaches used in the fight against cancer. This subject matter is limited to most current major treatments recognized recently in the Journal of Neuro-Oncolgy, plus I am including another group called immunostimulants.
In all, there are 17 therapies that can be placed into four approaches which treat cancer. The four Immunotherapeutic Approaches herein are:
I. Vaccination
II. Cellular
III. Immunomodulation
IV. Immunostimulants
Part II addresses a cellular immunotherapeutic approach using Adoptive T-cell transfer chimeric antigen receptor-engineered T cell (CAR-T Therapy). This discussion is broken down into three subsections: Niche, Potential Competition with DCVax, and Potential Collaboration with DCVax.
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A. CTL-019 (Adoptive T-cell transfer Chimeric antigen receptor-engineered T cell — Aka: CAR-T)
i. Potential Niche for CTL-019
CTL-019 is allegedly owned by Novartis Pharmaceuticals; however, Juno Therapeutics claims rights to the same technology via St. Jude’s patent.
In this therapy, T-cells from the patient (autologous cells) are extracted from the patient’s blood and infected with a virus that encodes the components of antigen receptors on T-cell surfaces which can lock onto CD19 antigens located on B-cell tumor surfaces.
CD19 antigens are a protein encoded by the CD19 gene, and they are also located on normal B-cells — a type of white blood cell that assists in immune regulation and balance. Because B-cell lineage leukemias and lymphomas rarely lose CD19 antigen expression, it has become the target for a variety of immunotherapeutic agents.
Unfortunately, when one successfully targets CD19 antigens on B-cell tumors, normal B-cells are also eliminated. Consequently, after treatment with CTL-019, many patients require intravenous immunoglobulins for long-term B-cell aplasia, particularly where chronic infections predominate.
CTL-019 is expected to result in a "cytokine storm,” otherwise known as cytokine release syndrome (CRS); as a result, a few days of hospitalization are initially required for therapeutic management. CRS is a serious condition that causes patients to experience high fevers, nausea, myalgias, capillary leak, hypoxia, and hypotension. CRS severity in patients is often related to their tumor load at the time of infusion with CTL-019, dosing and the proliferative capacity of T-cells. Delayed appearance of cytokine release syndrome (aka: tumor lysis syndrome) adverse events can also occur up to 50 days after infusion. CRS is often treated by administering anti-interleukin-6 antibody Actemra (tocilizumab; Roche/Chugai), a rheumatoid arthritis drug. It goes without saying that this multistage therapy is extremely expensive.
Preliminary study results show 27 of 30 pediatric and adult patients with relapsed/refractory (r/r) Acute Lymphoblastic Leukemia (ALL), 90% experienced complete remissions with personalized cell therapy, CTL019 sustained remissions of up to two years in r/r Acute Lymphoblastic Leukemia patients with six-month event-free survival of 67% and overall survival of 78%. Comparisons to historical standards of care are nearly impossible because there are so many different subclassifications for relapsed/refractory Acute Lymphoblastic Leukemia.
Conclusion:
CTL-019 therapy is a treatment for patients with advanced B-cell acute lymphoblastic leukemia (ALL), and possibly other B-cell leukemias and lymphomas -- but not other types of leukemias or cancers. It is an option for patients who demonstrate very resistant acute lymphoblastic leukemia. Roughly 85 percent of acute lymphoblastic leukemia cases are treated very successfully with standard chemotherapy. For the remaining 15 percent, representing a substantial number of children in the United States, chemotherapy only works temporarily or not at all. CTL-019 is not a treatment for newly diagnosed B-cell leukemia, only for patients who are not responding to chemotherapy and whose disease has returned after a bone marrow transplant.
ii. Potential Competition between DCVax and CTL-019
Currently, CTL-019 does not present any near-term competition for DCVax. Nevertheless, DCVax-Direct and/or advanced DCVax-L will certainly be studied and likely proven efficacious against against bloodborne cancers; in which case, DCVax may provide a superior, nontoxic and low-cost alternative to CTL-019 for recurrent/refractory leukemia(s) and lymphoma(s). This is particularly true because CTL-019 only targets one tumor antigen, and therefore it is vulnerable to tumor escape (previously described in Part I). Whereas DCVax prevents tumor escape by utilizing the complete compliment of tumor antigens. Preclinical studies already confirm dendritic therapeutic benefits extend to blood-borne cancers.
(In the future, Car-T therapy can be improved through many methods currently under investigation. For example, engineering T-cells with additional antigen receptor(s) located on tumors but rarely found on normal cells might prevent B-cell aplasia.)
iii. Potential Collaboration between DCVax and CTL-019
a. Theoretically, there is the possibility that CTL-019 could be utilized/licensed by Northwest Biotherapeutics for use in alternative dendritic cell maturation. While there are many factors that make DCVax therapy a potent weapon against cancer, DC partial maturation is the cornerstone for DCVax dendritic therapeutic potency. Coincidentally, "Activated T cells express costimulatory molecules CD27, CD70 and CD40L that could potentially interact with their counterparts on dendritic cells (DCs). CD40L-CD40 interactions are known to induce upregulation of costimulatory molecules on DCs and thereby activating them and increasing their antigen-presenting abilities.... After 48h co-culture, DCs have increased expression of maturation markers (CD83, CD80, CD86) compared to before co-culture. Karlsson H., Gustafsson W., Olsson-Strömberg U., Savoldo B., Dotti G., Loskog A. CAR-T cells induce DC maturation via a cell-cell contact-dependent process and enhance their ability to stimulate T cell responses."
b. Additionally, because DCVax-Direct can overcome the immunosuppresive effects of cancer and reestablish balanced immunity in patients, CTL-019 and future Car-T therapeutic effects may be enhanced by patient pretreatment with DCVax-Direct. Moreover, where pretreatment with DCVax substantially reduces tumor load, followup CTL-019 therapy related side effects should be significantly diminished. This presumption is made due to the fact that severe CTL-019 induced cytokine release syndrome is more likely in patients with high tumor load at the time of infusion. DCVax pretreatment/first line therapy in turn may reduce the need for hospitalization and emergency pharmaceutical intervention after CTL-019 infusion.
Conclusion:
Preclinical trials could be conducted to prove or disprove the aforementioned collaborative hypotheses.
