Table of Contents
Introduction
Y-traps are recently invented type of bi-functional immunotherapeutic agents which comprise of Y-shaped targeting antibody fixed in a trap which can deactivate an immunosuppressive molecule. In this technology, a trap which is based on the natural receptor to TGFβ has been developed with an objective to sequester TGFβ. The technology involves the use of two different antibodies, namely CTLA-4 antibody and PD-L1 antibody, fused in TGFβ traps of two different types of Y-traps. The CTLA4-targeted Y-trap is meant to delete Tregs while PD-L1-targeted Y-trap prevents suppression of the immunity and thus inhibiting the growth of tumors (Scicasts, 2018).
Y-trap technology, as the new cancer immunotherapy technology can be called, has been invented by the Johns Hopkins’ Researchers. The invention follows after it was found out that immune checkpoint inhibitors fail in the treatment of cancer because tumors have the ability to a growth factor-β termed as TGFβ and with transforming capabilities. These transforming growth factors-β have much to regulate immunity in the body and in developing T-cells also known as Tregs which also suppresses and regulates body’s immunity. A correlation between the activation pathway of the TGFβ in several cancers and the Treg signature, FOXP3 has been noted (Johns Hopkins University School of Medicine, 2018). Tregs are the main reason for tumors, a big reason why poor outcomes are recorded in various types of cancer. The invention of the Y-traps was thus accelerated by the need to find a solution to this challenge. The invented class of these immunotherapeutic agents is believed to be very effective in boosting the power of the body immune system in fighting cancer.
Historical perspectives of immunotherapy
It is believed that vaccination development, an innovation that has been used since the 18th century, has impacted positively on modern medicine. By third century BC, China had used variolation techniques to prevent smallpox. During the 18th century, Edward Jenner, a European researcher in medicine, developed a vaccine against cowpox which turned out to have the ability of smallpox prevention. The prove of germ theory by Louis Pasteur, and Joseph Lister which was formally proposed by Antonio Bassi in 1844 led to the development of infectious disease postulates by Robert Koch. By this time, researchers were aware that diseases were caused by pathogens and that when weakened or dead pathogens were inoculated in the body, they provoked protective immunity in the host. Since then various vaccines were developed in the 19th century to prevent various diseases such as plague, cholera, tuberculosis, and others (William et al., 2017). The first successful immune-based treatment for cancer was developed in the late 19th century by Dr. William B. Coley which included a Gram-positive and Gram-negative bacteria combination; that is, heat-killed S. pyogenes and heat-killed B. prodigious (the S. marcecsens). In 1957, Graham developed a cancer vaccine which was a tumor-specific antibody. From this innovation, several cancer immunotherapies were developed in the subsequent years. In the years 1998 and 2001, Schreiber and colleagues provided prove of T cell-mediated tumor-specific immune surveillance evidence and tumor immune escape (William et al., 2017).
Immuno-oncology was accepted by clinical practitioners in the year 2011. Brunet and colleagues were the first to identify cytotoxic T-lymphocyte antigen 4 (CTLA-4) in the year 1987, but its critical immune checkpoint and its ability to treat cancer were unknown. In 1993, a strategy that involved generation of genetically modified T-cells was adopted in the treatment of cancer. The CAR strategy was then embraced (William et al., 2017). Tumor antigen-specific single-chain immunoglobulin variable region (scFv) would be linked to CD3-ζ and or other costimulatory signaling domains such as CD28. By 2016, about four different drugs had been approved to treat lung cancer, renal cell carcinoma, and other bladder cancers. Now, the Johns Hopkins’ researchers have just invented a type of bi-functional immunotherapeutic agents which comprise of Y-shaped targeting antibody fixed in a trap which can deactivate an immunosuppressive molecule – the Y-traps – for the treatment of cancer (Researchers, 2018).
Cellular Mechanism of immunotherapy
The activation of T- or B- lymphocytes, the adaptive immunity cells, by an antigen occurs after the antigen is recognized through first signal or second signal also known as the antigen-specific receptor or the co-inhibitory molecules on other cells respectively. Antigens in peptide form are recognized by the T-lymphocytes as a molecular complex consisting of major histocompatibility complex molecules on other cells which get lysed by effector T-cells. As well the second signal cell to cell interaction is molecular specific which involves receptor-ligand interactions. Lymphocyte molecules act as receptors while the other cells present the ligand molecules and their interactions may result in boosting their activation or inhibiting their initiated activation (Antonio, 2017).
Physiologically these signals create a negative feedback mechanism which prevents too strong activation of the immune. Inhibitory receptors can be blocked by the antibodies against them and thereby causing activation or reactivation of lymphocytes which in turn expresses the CTLA-4 molecule, a molecule CD28 molecular homolog. CTLA-4 molecule initiates negative feedback mechanisms which prevent too strong activation of the immune. Due to the high affinity of CTLA-4 for B7 molecule interaction when compared with CD28 it follows that the initial activation of lymphocytes is followed by an activation brake psychologically. Therefore, these cell interaction results in negative feedback mechanisms blockade, T-lymphocytes activation also called anti-CTLA-4 blockade or energized T-lymphocytes reactivation also called anti-PD-1 or anti-PD-L1 blockade and which can clinically be used as a cancer treatment or to control tumor diseases – cancer immunotherapy (Antonio, 2017).
Applications of immunotherapy
Immunotherapy is dependent on the power of the patient’s immune system when fighting diseases. With cancer, different techniques have been adopted and include the following:
Chimeric antigen receptor (CAR) T-Cell Therapy
The technique also referred to as adoptive cell transfer therapy is applied in the treatment of blood cancers. Tisagenlecleucel (Kymriah) treats acute lymphoblastic leukemia while Axicabtagene ciloleucel (Yescarta) treats large B-cell lymphoma such as non-Hodgkin’s lymphoma in adults. In this therapy, T-cells are reprogrammed to fight cancer cells. A patient is taken through a leukapheresis process after which chimeric antigen receptors (CAR) are added to the blood to seek out and destroy targeted cancer cells. Some of the side effects associated with this therapy include very high fever, confusion and low blood cell count which results from the many replications of the CAR T-cells (WebMD, 2017).
Tumor-infiltrating lymphocytes (TIL) Therapy
These cells are made by the patients’ immune system. In this therapy, the doctor obtains TILs from the patients’ tumor tissue and multiplies them in the lab. Cytokine proteins are then added which boost the cells ability to fight cancer. TILs are then added to the patients’ body after chemotherapy treatment to lower T cell numbers (WebMD, 2017). The technique is being adopted to treat colorectal and ovarian cancers.
Immune Checkpoint Inhibitors
The immune system is supposed to recognize and destroy pathogens in the body. It has checkpoints, molecular brakes which help it to take control. However, cancer cells can turn these checkpoints on or off and hence interfere with the immune system. Therefore, these drugs, immune checkpoint inhibitors, assist the immune system in protecting the body. Immune checkpoint inhibitors include: PD-1 or PD-L1 inhibitors which target PD-1 or PD-L1 on the T-cells. The technique treats lung, kidney and bladder cancers. CTLA-4 inhibitors are other immune checkpoint inhibitors which turn off CTLA-4 checkpoints found on T-cells (WebMD, 2017). It is used to treat melanoma.
Regulatory aspects from FDA
The newly developed Immunotherapy technology in cancer treatment was approved by FDA to treat cancer diseases based on genetics rather than type (McDaniels, 2018). FDA proposed the treatment to be used for patients who are up to 25 years of age. Some of the cancers the drug can treat include colon, stomach, and ovarian cancers.
Future directions
The Y-trap technique was a clever invention. The Y-trap disables the CTLA-4 function and as well disrupts the TGFβ feedback loop and thereby inducing and maintaining Tregs in a tumor. Tregs in these tumors could not be reduced through the clinical use of ipilimumab, an action the Y-trap is capable of. There is thus a possibility that in future there would be no spread of the ipilimumab and pembrolizumab unresponsive tumors with the use of the Y-trap technique in clinics (Scicasts, 2018). It is because the immune dysfunction mechanism is similar to various types of cancer and thus if one type of cancer disease is treated effectively through this Y-trap approach, it follows that all other cancers which a similar immune dysfunction mechanism would as well be treated using the same technique.
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- Johns Hopkins University School of Medicine. (2018). Team develops new technology platform for cancer immunotherapy. Medicalxpress.com.
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- Researchers, J. (2018). Johns Hopkins Researchers Invent New Technology for Cancer Immunotherapy – 03/01/2018.
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