Monday, March 9, 2020

"TEACHING" T-CELLS TO KILL CANCER TUMORS

Written by: Dr. Robert Bard, NY Cancer Resource Alliance editorial staff & AngioMed Publications


"With Immunotherapy, we take advantage of the body's own natural defenses that's a lot smarter than any doctor... (it) provides the best clues for the development for effective cancer treatments for patients who cannot be helped by current modalities"- Dr. Steven Rosenberg, Natl. Cancer Inst. ("Father of Immunotherapy")


INTRODUCTION
CAR T-cell therapy is a type of immunotherapy- otherwise called a type of adoptive cell transfer. CAR T-cell therapy is a very complex and specialized treatment where a specialist collects and makes a small change to your T cells. These then target the cancer cells.  It is available as a possible treatment for some children with leukaemia and some adults with lymphoma. People with other types of cancer might have it as part of a clinical trial. 

To understand CAR T-cell therapy more, it helps to understand what T cells do. White blood cells called lymphocytes play an important part in fighting infection and diseases, including cancer. There are different types of lymphocytes. T cells are one type. T cells move around the body to find and destroy defective cells. When you come into contact with a new infection or disease, the body makes T cells to fight that specific infection or disease. It then keeps some in reserve so that if you come across the infection again your body can recognize it and attack it immediately. [aa]

T CELLS in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the anti-tumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. (In the review from Springer Nature), we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells infighting cancers. 

T cells play central roles in cell-mediated adaptive immunity. Since researchers identified the molecular evidence of T cell receptors (TCRs) in the 1980's, the recognition of antigens by TCRs has been heavily investigated, and the molecular mechanisms governing this process have been elucidated, laying the foundation for cancer immunotherapy. [2]



DR. HASAN'S T CELL ENGINEERING RESEARCH PROCESS
The pursuit of harnessing the body’s immune system to treat cancer was first established by Dr. William Coley in 1891 and continues to be applied as an expanding innovation in cancer treatment today.  Today, a vast number of immunotherapies have been developed- such as monoclonal antibodies (used to block abnormal proteins in a cancer cell), checkpoint inhibitors that remove barriers to anti-tumour immunity, oncolytic virus therapy, cancer vaccines and T-cell therapy. [1]

NYCRA NEWS features a wide set of focus points in the world of cancer care including research innovations- and the experts behind them.  This review of cancer immunotherapy brings us to the work of DR. AISHA HASAN - innovative research specialist in clinical pursuit of a cancer immunotherapy breakthrough by harnessing the body’s T-cells. 

As an oncologist, Dr. Hasan underwent her training at Sloan Kettering Cancer Center in Hematology Oncology.  She spent over 13 years researching T-cell therapies to target deadly cancers that occur in patients who have received bone marrow transplants.  Her exploratory work involved implementing T-cell therapies in human clinical trials.

Throughout her research process, T-cell therapies were applied on a broader scale to active patients who had deadly infections after receiving bone marrow transplantation and patients who developed any kind of EBV (Epstein-Barr virus) related malignancies..  Her expertise in the study of T-cell biology, immune deficiencies and cellular immunity was very insightful in developing many other modalities for treating cancer using T-cells.

Her tenure at Sloan Kettering Cancer Center was spent working with several research groups to develop bi-specific antibodies, and TCR mimic antibodies that can then be made into engineered T-cells, which would then target antigens expressed on tumor cells. One of those antigens is called WT-1. These types of engineered cells are living drugs. They are medicines that can be introduced into the body which can multiply upon encountering the targeted antigens on tumor cells, and thereby provide ongoing protection against cancer to patients in need.  As head of clinical development at GSK, she has promoted gene engineered cellular therapy and has enabled the development of novel T-cell therapies for treating solid tumors. Using innovative study designs has allowed for multiple cohorts of patients with different tumor types to be treated with T-cells.  These same therapies are now currently part of actual clinical trials.


EARLY CONCEPTS
“Adoptive cell transfer” is an immunotherapeutic approach which involves the ex vivo expansion and re-infusion of antigen-specific (AG-specific) T cells, and has been used in various forms. The first recognition that adoptive T-cell therapy could be a potentially curative treatment for cancer came with the initial reports by Steve Rosenberg et al [3], describing complete regression of bulky tumors in patients with metastatic melanoma infused with ex-vivo expanded T-cells extracted from surgically resected tumors, also called tumor infiltrating lymphocytes.  T-cells used for treatment can also be genetically redirected toward tumor associated antigens by modification with a T-Cell Receptor (TCR) or Chimeric Antigen Receptor (CAR).

Dr Hasan elected to focus the start of her career in the research study of T-Cells because of a personal belief in this avenue of treatment. Since the early days of her fellowship in oncology, she carried the immunologists' belief that cancer happens when one's immunity goes down-- giving opportunity for mutated tumor cells to grow.   The body's design is to get rid of mutated abnormal cells, thanks to specifically to the T-cells in the immune system as the main fighters against any abnormal cells.
A large portion of the insights in the biology of T-cell killing were derived from the extensive research conducted on T-cells during the AIDS epidemic in the 1980's.  These insights paved the way for the application of T-cell therapies in cancer.

Dr. Hasan expressed that during the early days of this T-cell therapy research, there was little indication that showed signs of becoming more than a theory for a viable therapy, let alone a large scale development of therapies against cancer.  Scientists saw it more as a way to understand how to influence the immune system.  "We have found the T-cells within the body to take care of cancer- and as a result of this research, one thing led to another and here we are... genetic engineering! We are now literally engineering T-cells to express molecules on their surface that arm them to then go and seek out and kill the cancer cell."


RESPONSE DRIVEN PATIENT DATA 
Currently, Dr. Hasan's research prevails the search for a constant end point within open label trials.  By this, she takes the T-cells from select patients with advanced or stage four cancers, modifying them externally and re-introducing them back into the body. They are all part of phase one trials- hence, patients who have exhausted all prior therapy options. Analysis of this defined set of patients are part of a fully powered study whereby the statistical design is already pre-established. There are planned analyses that would be conducted at different time points for the different studies that are ongoing. She and her fellow researchers expect significant data to arise in the next two years.Dr. Hasan started with a small experiment with engineering cells in a certain way. The next wave of engineering for these T-cells would address some of the barriers to the efficacy of these cells in the tumor microenvironment in order to incorporate multi-component engineering technologies in order to affect additional molecules within the cells that will address some of the limitations. Next is to work with a pre-clinical group to actually look at other targets and bring them to the clinic.  These would also be either CAR or TCR-modified T-cells (for the first time) in human studies within the next year to two.


TIP OF THE ICEBERG
The initial success achieved by all researchers during this time have set the stage for the main development of T-cell therapies for cancer.  According to Dr. Hasan, "what we've been able to do right so far with T-cell therapies is cancer antigens that are ubiquitously or constantly expressed on the surface of the cell.  However, the bulk of cancer associated antigens present on solid tumors are in fact intra-cellular, and not easily targeted. They cannot be targeted with the CAR-T that have been approved thus far.  Therefore, T-cells engineered to express TCRs are attractive as a therapeutic approach because they are able to target intra-cellular antigens associated with tumor cells. 
Meanwhile the issue still remains that (so far) we have not been able to attack, cure or get to a good efficacy with solid tumors.  Cancer cells typically have a very thick or dense conglomeration of tumor cells that are embedded within a very immune inhibitory micro-environment with very little blood supply... cells within the tumor actively inhibit the activity of T-cells.  So a lot of our efforts at the moment are focused on the issue of the tumor micro-environment and how to target solid tumors with T-cells to make them more effective."

To develop a publicly accessible (and FDA accepted) cancer immunotherapy drug, the main objective of clinical researchers needs to keep with the plan to 'make this therapy not so personalized'.  By this, they need to overcome that barrier of autologous cells to then move into creating an off-the-shelf therapy. 

During her laboratory research work at MSK, Dr. Hasan's research team led the path of experimentation toward what might just be an off-the-shelf approach.  At GSK, she is in the exploratory phase of testing  T-cells that have been  engineered in order to overcome immune inhibitory molecules within  tumors.  Combination approaches with antibodies or other small molecules with T-cells could further empower   the infused T-cells to actually overcome the inhibition within the tumor micro-environment and achieve complete remission of cancer.  Another wave of development in this space will deliver modalities that will enhance the T-cell manufacturing capability, thereby extending this therapy to many more patients in need. "We look at these T-cells as living medicine and as such,  engineering them means  they need to be grown, frozen down and preserved for future use. It's something that is quite a cumbersome process despite many companies investing in closed mechanized systems to actually grow these T-cells. But it is far from being one of those situations where it's widely applicable or  available."

In a 2018 AACR conference, Dr. Carl June started his presentation by saying “I think we’re about five years behind where checkpoint therapies are with CAR T cells.”   This mirrors Dr. Hasan's statement about the study as having 'a long way to go'.   In 2012, Dr. June achieved the first successful CAR T-cell therapy with CD19 CAR T to a patient with acute lymphoblastic leukemia who remains in complete remission today. So far, two different types of CAR T-cell therapies have been approved by the U.S. Food and Drug Administration (FDA). Both have been approved to treat blood malignancies: axicabtagene ciloleucel (Yescarta) has been approved for the treatment of a certain kind of non-Hodgkins lymphoma, and tisagenlecleucel (Kymriah) has been approved for the treatment of certain types of leukemia and Non-Hodgkins Lymphoma. [5]


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REFERENCES:

[aa] CAR T-cell therapy- (origin: Cancer RESEARCH uk)
© Cancer Research UK [2002] All right reserved. Date uploaded (3/9/2020).
Cancer Research UK is an independent organization from the NY Cancer Resource Alliance and the publisher(s) of this site- and a source of trusted public information for all.
2) https://www.nature.com/articles/s41392-019-0070-9#citeas From: "Genetically Engineered T Cells For Cancer Immunotherapy" source: https://rdcu.be/b2IJ9 by: Dan Li, Xue Li, Wei-Lin Zhou, Yong Huang... 
3) NIH; Dr. Srteven A Rosenberg, An Immunotherapy Pioneer Tells All (by Emily Petrus, NINDS)



CONTRIBUTING WRITER

ROBERT L. BARD, MD, PC, DABR, FASLMS - Advanced Imaging & Diagnostic Specialist
Having paved the way for the study of various cancers both clinically and academically, Dr. Robert Bard co-founded the 9/11 CancerScan program to bring additional diagnostic support to all first responders from Ground Zero. His main practice in midtown, NYC (Bard Diagnostic Imaging- www.CancerScan.com) uses the latest in digital Imaging technology has been also used to help guide biopsies and in many cases, even replicate much of the same reports of a clinical invasive biopsy. Imaging solutions such as high-powered Sonograms, Spectral Doppler, sonofluoroscopy, 3D/4D Image Reconstruction and the Spectral Doppler are safe, noninvasive, and does not use ionizing radiation. It is used as a complement to find anomalies and help diagnose the causes of pain, swelling and infection in the body’s internal organs while allowing the diagnostician the ability to zoom and ‘travel’ deep into the body for maximum exploration.



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