Engineered T Cells Therapies versus Cancer

Therapies based on engineered T cells are poised to gain widespread academic, industrial, and governmental approval to fight various cancers. Collaborations between academia and biotechnology help scientists understand how, when, and where to deploy these new and exciting therapies in order to maximize clinical benefits, and minimize side effects in cancer patients.

Engineered T Cells to Fight Cancer: Layla Richards

Engineered T Cells to Fight Cancer: Layla Richards

Engineered T Cells to Fight Cancer: Layla Richards

Engineered T Cells to Fight Cancer: Layla Richards

The first case that utilized gene modification to treat human disease was reported in 2015 from a clinical trial including twelve people with HIV. In the second recorded case of gene modification, a child recently received gene modified immune T cells from an unrelated person to treat acute lymphoblastic leukemia (ALL). One-year-old Layla Richards now shows no signs of the cancer returning (1,2).

In a December 5, 2015 report, the American Society of Hematology recounted that all conventional treatments, including Blinatumomab (a biopharmaceutical drug targeting CD19 antigen present on B cells), and bone marrow transplantation from a mismatched, unrelated donor failed to clear cancer cells in Layla (3). However, Layla’s response to the experimental therapy is promising (3). To date Layla has not experienced any severe adverse effects (e.g. cytokine release syndrome).

Engineered T Cells to Fight Cancer: The family of one-year-old Layla Richards is pictured below. Layla was the second recorded case of gene modification.

Engineered T Cells to Fight Cancer: The family of one-year-old Layla Richards, the child who was the second recorded case of gene modification. Layla received gene modified immune T cells from an unrelated person to treat acute lymphoblastic leukemia (ALL).

(Fig.I): Engineered T Cells to Fight Cancer: Layla received gene modified immune T cells from an unrelated person to treat acute lymphoblastic leukemia (ALL).

Layla’s mother, Lisa: I thought it was bad news but then he said ‘it’s worked’ and I just cried happy tears…

I consider ourselves lucky that we were in the right place at the right time to get a vial of these cells. We always said that we had to try new things as we didn’t want to be saying ‘what if?…

Hopefully Layla will stay well and lots more children can be helped with this new treatment”

Layla was cancer free two months after the treatment and received a second bone marrow transplant. She was well enough to return home one month after the second transplant. Engineered T cell therapy from a mismatched, unrelated person seems to provide at least a temporary cancer fighting solution for Layla until a well-matched bone marrow donor is found. However, the long-term ability of engineered T cell therapy to cure Layla remains uncertain.


Engineered T Cells | Layla Richards

(Fig.II) Layla Richards

  • Born healthy at 7lb 10 in June 2014.
  • No problems during pregnancy.
  • Acute Lymphoblastic Leukaemia (ALL) detected at 14 weeks old.

French biotech company Cellectis, alongside investigators at University College London, the teams at GOSH and the UCL ICH, had been developing ‘off-the-shelf’ banks of donor T-cells known as UCART19 cells.

  • Healthy T-cells are obtained from a donor.
  • New genes are added to the donor T-cells, arming them against leukaemia.
  • Using scissor-like molecular tools (TALEN®), specific genes are added to make the T-cells behave specifically:
    1. The cells become invisible to a powerful leukaemia drug that would kill them;
    2. they are reprogrammed to only target and fight against leukaemia cells.

  • Treatment consists of 1ml of UCART19 cells delivered via intravenous line in around 10 minutes.
  • After delivery, the patient spends several months in isolation due to an extremely weak immune system.
  • Several weeks elapse before signs appear that the treatment is working.
  • Once the leukaemia cells have been removed, a bone marrow transplant is given to replace the entire blood and immune system which had been wiped out by the process.
  • Frequent checks are performed to ensure that the bone marrow cells are healthy and blood counts continue to normalize.

  • Full clinical trials funded by Cellectis are now being planned to test UCART19 cells in larger groups of patients.

    “Cellectis main objective is to provide cancer patients with an accessible, cost-effective, off-the-shelf allogeneic CAR-T therapies across all geographies. With clinical trial for the first gene-edited UCART on the horizon, it could be the beginning of a revolution in cancer immunotherapy,” says Dr. André Choulika, Chairman and CEO of Cellectis.

Chimeric antigen receptor (CAR) modified T cells (employed in Layla’s case) is one of three types of engineered T cells combating cancer. Tumor infiltrating lymphocytes and T cell receptor (TCR) modified T cells are also used in humans (4).

Types of engineered T cells

Types of engineered T cells

Types of engineered T cells

Types of engineered T cells

  • Tumor infiltrating lymphocytes (TIL)

  • Tumor infiltrating lymphocytes (TIL)

  • Tumor infiltrating lymphocytes (TIL)
  • Tumor infiltrating lymphocytes (TIL)

Over several decades scientists studied and slowly developed tumor infiltrating lymphocytes. They are isolated from a surgically excised tumor mass, expanded in vitro, then infused into cancer patients. A current phase III clinical trial focuses on comparing tumor infiltrating lymphocytes to standard ipilimumab in patients with metastatic melanoma (5). Tumor infiltrating lymphocytes are not yet on the market. However, Lion Biotechnologies currently focuses on commercializing engineered T cells based on tumor infiltrating cells (6).

Engineered T Cells to Fight Cancer: Tumor infiltrating lymphocytes (TILs) technology TILs are white blood cells that have left the bloodstream and migrated into a tumor. TILs, when numerous, are considered to be prognostically significant. Therapeutic TILs is a preparation of cells, consisting of autologous tumor infiltrating lymphocytes that are manipulated in vitro and, upon administration in vivo, re-infiltrate the tumor to initiate tumor cell lysis. In vitro, TILs are isolated from tumor tissue and cultured with lymphokines such as interleukin-2. The therapeutic TILs are then infused into the patient, where, after re-infiltration of the tumor, they may induce lysis of tumor cells and tumor regression. The use of therapeutic TILs is considered a form of adoptive immunotherapy.

(Fig. III) Engineered T Cells to Fight Cancer: Tumor infiltrating lymphocytes (TILs) technology TILs are white blood cells that have left the bloodstream and migrated into a tumor. TILs, when numerous, are considered to be prognostically significant. Therapeutic TILs is a preparation of cells, consisting of autologous tumor infiltrating lymphocytes that are manipulated in vitro and, upon administration in vivo, re-infiltrate the tumor to initiate tumor cell lysis. In vitro, TILs are isolated from tumor tissue and cultured with lymphokines such as interleukin-2. The therapeutic TILs are then infused into the patient, where, after re-infiltration of the tumor, they may induce lysis of tumor cells and tumor regression. The use of therapeutic TILs is considered a form of adoptive immunotherapy

  • T Cell Receptor (TCR) modified T cells

  • T Cell Receptor (TCR) modified T cells

  • T Cell Receptor (TCR) modified T cells
  • T Cell Receptor (TCR) modified T cells

The TCR modified T cell is another option among these experimental therapies. They are produced from periphery blood lymphocytes and introduced by cancer-specific TCR genes through viral or non-viral methods, with the potential to kill cancer cells.

TCR modified T cells have been studied and applied in a variety of cancers. Unfortunately, they have led to serious adverse events in some treated patients. As a result, TCR modified T cells are not yet on the market. Several pharmaceutical and biotechnology companies such as GlaxoSmithKline/Adaptimmune, Catapult Cell Therapy, and Medigene continue to test these cells for treating several types of cancers in early phase clinical trials.

Engineered T Cells to Fight Cancer: T Cell Receptor (TCR) TCRs are proteins that allow T cells to identify cancer targets presented on the surface of cancer cells or inside cancer cells. Endogenous TCRs that are specific to a cancer can be isolated and then engineered into a large number of T cells that recognize and attack various types of solid and hematologic cancers.

(Fig.IV) Engineered T Cells to Fight Cancer: T Cell Receptor (TCR) TCRs are proteins that allow T cells to identify cancer targets presented on the surface of cancer cells or inside cancer cells. Endogenous TCRs that are specific to a cancer can be isolated and then engineered into a large number of T cells that recognize and attack various types of solid and hematologic cancers.

  • Chimeric antigen receptor (CAR) modified T cells

  • Chimeric antigen receptor (CAR) modified T cells

  • Chimeric antigen receptor (CAR) modified T cells
  • Chimeric antigen receptor (CAR) modified T cells

The CAR modified T cell is the experimental therapy which proved (at least temporarily) effective in treating Layla’s leukemia. These T cells are engineered by introducing chimeric antigen receptors consisting of two domains: an extracellular cancer antigen binding domain that specifically recognizes cancer cell surface proteins without requiring MHC-restricted antigen recognition by T cells or antigen presentation by cancer cells, and an intracellular signaling domain that mimics native TCR signaling.

Preclinical data and early stage clinical trials show that CAR modified T cells have the potential to combat a variety of B cell malignancies. In fact, in July of 2014, the first personalized cellular therapy for cancer was awarded the U.S. Food and Drug Administration’s Breakthrough Therapy designation resulting in the FDA’s expedited development and review of the treatment (7). The personalized therapy, developed by the University of Pennsylvania, employed CAR modified T cell therapy to treat acute lymphoblastic leukemia. There are nearly 20 ongoing clinical trials for treating B cell malignancies which are actively recruiting patients (8).

Additionally, there are several current clinical trials utilizing CAR modified T cells to treat other types of cancers. For example: acute myeloid leukemia (NCT01864902 and NCT02159495), multiple myeloma (NCT01886976), Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NCT01192464 and NCT01316146), glioblastoma (NCT02209376), and breast cancer (NCT1837602).

Many pharmaceutical and newly formed biotechnology companies are investing heavily in the development of various forms of CAR modified T cells. However, commercialized products for CAR modified T cells do not yet exist.


Engineered T Cells to Fight Cancer: T cell immunotherapy involves engineering a patient’s own cells to recognize a protein present in cancer cells, enabling them to seek out and destroy the cancer. The technique involves filtering white blood cells called T cells from a patient’s blood and introducing a new gene into those cells. A disabled virus called a vector is used to carry the gene inside the T cells and insert it into the cells’ genomes. The gene programs the T cells to make a chimeric antigen receptor (CAR), which enables them to recognize a specific protein that’s present in cancer cells. The CAR T cells are then grown in the laboratory and infused back into the patient, where they seek out and destroy the cancer.

(Fig.V) Engineered T Cells to Fight Cancer: CAR T cell immunotherapy involves engineering a patient’s own cells to recognize a protein present in cancer cells, enabling them to seek out and destroy the cancer. The technique involves filtering white blood cells called T cells from a patient’s blood and introducing a new gene into those cells. A disabled virus called a vector is used to carry the gene inside the T cells and insert it into the cells’ genomes. The gene programs the T cells to make a chimeric antigen receptor (CAR), which enables them to recognize a specific protein that’s present in cancer cells. The CAR T cells are then grown in the laboratory and infused back into the patient, where they seek out and destroy the cancer.

  • Universal CAR modified T cells

  • Universal CAR modified T cells

  • Universal CAR modified T cells
  • Universal CAR modified T cells

There are currently two approaches to engineer CAR modified T cells: autologous patient-specific T cells for personalized therapy, and allogeneic universal T cells for larger patient groups, which has the potential for widespread application at a lower cost. Layla’s case is the first to employ the universal T cells’ approach. The following three strategies have been utilized to engineer universal T cells (called UCAR19) and overcome allogeneic transplant.

Genetic editing approach with transcription activator-like effector nucleases (TALENs) silenced the expression of the endogenous TCR on UCAR19 T cells and to eliminate the risk of TCR mediated graft versus host disease. Additionally, lympohdepleting agent, alemtuzumab, was administered to Layla to deplete CD52 expressing mature lymphocyte. This eliminates the risk of host lymphocytes mediate rejection of mismatched UCAR19 T cells. Lastly, TALENs edit out CD52 expression on UCAR19 T cells, avoiding the risk of an alemtuzumab attack. This first clinical application of universal CAR T cells in the human body offers a T cell strategy roadmap for further clinical studies and trials.

The Loncar Cancer Immunotherapy Index

The Loncar Cancer Immunotherapy Index

The Loncar Cancer Immunotherapy Index

The Loncar Cancer Immunotherapy Index

In April of 2015, The Scientist published an article overviewing the enthusiasm surrounding CAR modified T cell immunotherapy. The ongoing frenzy of scientific and market related interest in the therapy illuminates the primary goal of replacing standard cancer treatments (9). Brad Loncar, notable biotech investor and analyst, developed the Loncar Cancer Immunotherapy Index to track the structure, conduct, and performance of pharmaceutical and biotechnology companies (10). The index provides metrics and reference to monitor awareness of immunotherapy, investment in the field, cancer patients’ progress.

The Loncar Cancer Immunotherapy Index (LCINDX)
Ticker Symbol LCINDX
Inception Date 3/18/2015
Index Provider Loncar Investments, LLC
Index Calculator Indxx, LLC
Total Holdings 30
Large Cap 5
Growth Biotech 25
Weighting Equal-weighted
Rebalanced Semi-annually
Reconstituted Semi-annually
Reported to Bloomberg, various others
Min. Market Cap $100 million
Index facts valid as of 12/21/2016

(Fig.VI) Engineered T Cells to Fight Cancer: The Loncar Cancer Immunotherapy Index seeks to track the combined performance of a basket of companies that develop therapies to treat cancer by harnessing the body’s own immune system. Immunotherapy is a transformational field within the biotechnology space that is expected to become a foundational treatment for cancer over the next ten years. The index will provide a metric to follow its progress as researchers advance new technologies for the benefit of courageous patients who fight the disease. It is an equal-weighted index containing both large pharmaceutical and growth-oriented biotechnology companies that are leading in this approach.

Challenges Ahead

Challenges Ahead

Challenges Ahead

Challenges Ahead
  • Long-term clinical benefits.
    Will engineered T cell therapy elicit an adequate long-term immune response to cancers?
  • Side effects.
    Many clinical studies show adverse effects in cancer patients treated with engineered T cells. These include cytokine release syndrome ranging from high fever, muscle pain, and unstable hypotension, respiratory failure and unexplained tissue toxicities.
  • Types of cancers treated by engineered T cells.
    It remains unclear whether implementation of engineered T cells is effective in cancers other than B cell malignancies.
  • Optimizing engineered T cells.
    What are engineered T cells’ composition: CD4 T cells, CD8 T cells, or a mixture of these? How do we track differentiation of engineered T cells, and how do we optimize dosage when utilizing such therapy? Is there an optimal formulation of engineered T cells for all types of cancer? What is the strategy for attenuating side effects and amplifying the clinical benefits of engineered T cells?
  • Manufacturing and delivering engineered T cells.
    Is it possible to engineer T cells with closed robotic automated systems? What is the optimal manner of delivery to physicians, and how do we educate clinicians in utilizing engineered T cells?

Conclusions

Conclusions

Conclusions

Conclusions

Engineered T cell therapies are poised to gain widespread academic, industrial, and governmental approval to fight various cancers. Clinical trials are rapidly expanding, and will likely aid in addressing common challenges in the near future. Collaborations in academia and biotechnology help scientists understand how, when, and where to deploy engineered T cell therapies. These efforts maximize clinical benefits and minimize side effects in cancer patients.

Image Credit

  • (Featured Image, Fig. I & Fig. II) One year old Layla Richards (shown with family in Fig. I). Layla is the second recorded case of “gene modification.” Layla received gene modified immune T cells from an unrelated person to treat acute lymphoblastic leukemia (ALL). from World first use of gene-edited immune cells to treat ‘incurable’ leukaemia [2015-11-05; NHS]
  • (Fig. III) Engineered T Cells to Fight Cancer: Tumor infiltrating lymphocytes (TILs) technology TILs are white blood cells that have left the bloodstream and migrated into a tumor. TILs, when numerous, are considered to be prognostically significant. Therapeutic TILs is a preparation of cells, consisting of autologous tumor infiltrating lymphocytes that are manipulated in vitro and, upon administration in vivo, re-infiltrate the tumor to initiate tumor cell lysis. In vitro, TILs are isolated from tumor tissue and cultured with lymphokines such as interleukin-2. The therapeutic TILs are then infused into the patient, where, after re-infiltration of the tumor, they may induce lysis of tumor cells and tumor regression. The use of therapeutic TILs is considered a form of adoptive immunotherapy. from Lion Biotech: Tumor Infiltrating Lymphocyte Therapy Could Be Paradigm Shift For Treatment Of Melanoma And Other Solid Tumors [2014-01; Melanoma Research Victoria]
  • (Fig. IV) Engineered T Cells to Fight Cancer: T Cell Receptor (TCR) TCRs are proteins that allow T cells to identify cancer targets presented on the surface of cancer cells or inside cancer cells. Endogenous TCRs that are specific to a cancer can be isolated and then engineered into a large number of T cells that recognize and attack various types of solid and hematologic cancers. from [2017. The Science of TCR. Kite Pharma]
  • (Fig. V) Engineered T Cells to Fight Cancer: CAR T cell immunotherapy involves engineering a patient’s own cells to recognize a protein present in cancer cells, enabling them to seek out and destroy the cancer. The technique involves filtering white blood cells called T cells from a patient’s blood and introducing a new gene into those cells. A disabled virus called a vector is used to carry the gene inside the T cells and insert it into the cells’ genomes. The gene programs the T cells to make a chimeric antigen receptor (CAR), which enables them to recognize a specific protein that’s present in cancer cells. The CAR T cells are then grown in the laboratory and infused back into the patient, where they seek out and destroy the cancer. from CAR T Cell Therapies Are a Growing Area of Research [2015.03.31. Julie Grisham. Memorial Sloan Kettering Cancer Center]
  • (Fig. VI) The Loncar Cancer Immunotherapy Index (LCINDX) from The Loncar Cancer Immunotherapy Index [2015; Loncar Investments]

Credit: English Text curated by Jinnah Griffin

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.

Wanqiu Hou is the Founder of Scientific HealthSense, a website based application in mining health data for a consumer service. He received his PhD from the Chinese Academy of Sciences. Dr. Hou has more than 10 years of experience in medical research, writing and communications.


The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.

The Michelson Medical Research Foundation's Groundwork blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.