intellectual vanities… about close to everything

Dramatic Boost To Immune Response With Engineered Artificial ‘Cells’

with one comment

Using artificial cell-like particles, Yale biomedical engineers have devised a rapid and efficient way to produce a 45-fold enhancement of T cell activation and expansion, an immune response important for a patient’s ability to fight cancer and infectious diseases, according to an advance on line report in Molecular Therapy.

Stimulatory particles (red) bound to activated T-cells (blue) as seen by fluorescence microscopy. Scale bar = 10 µm (Credit: Fahmy-Steenblock/Yale)

The artificial cells, developed by Tarek Fahmy, assistant professor of biomedical engineering at Yale and his graduate student Erin Steenblock, are made of a material commonly used for biodegradable sutures. The authors say that the new method is the first “off-the-shelf” antigen-presenting artificial cell that can be tuned to target a specific disease or infection.

“This procedure is likely to make it to the clinic rapidly,” said senior author Fahmy. “All of the materials we use are natural, biodegradable already have FDA approval.”

Cancer, viral infections and autoimmune diseases have responded to immunotherapy that boosts a patient’s own antigen-specific T cells. In those previous procedures, a patient’s immune cells were harvested and then exposed to cells that stimulate the activation and proliferation of antigen-specific T-cells. The “boosted” immune cells were then infused back into the patient to attack the disease.

Limitations of these procedures include costly and tedious custom isolation of cells for individual patients and the risk of adverse reaction to foreign cells, according to the Yale researchers. They also pointed to difficulty in obtaining and maintaining sufficient numbers of activated T-cells for effective therapeutic response.

In the new system, the outer surface of each particle is covered in universal adaptor molecules that serve as attachment points for antigens — molecules that activate the patient’s T-cells to recognize and fight off the targeted disease — and for stimulatory molecules. Inside of each particle, there are slowly released cytokines that further stimulate the activated T-cells to proliferate to as much as 45 times their original number.

“Our process introduces several important improvements,” said lead author Steenblock. “First, the universal surface adaptors allow us to add a span of targeting antigen and co-stimulatory molecules. We can also create a sustained release of encapsulated cytokines. These enhancements mimic the natural binding and signaling events that lead to T-cell proliferation in the body. It also causes a fast and effective stimulation of the patient’s T-cells — particularly T-cells of the cytotoxic type important for eradicating cancer.”

“Safe and efficient T-cell stimulation and proliferation in response to specific antigens is a goal of immunotherapy against infectious disease and cancer,” said Fahmy. “Our ability to manipulate this response so rapidly and naturally with an “off the shelf” reproducible biomaterial is a big step forward.”

Fahmy was recently awarded a five-year National Science Foundation (NSF) Career Award for work on this process and ways of engineering biomaterials to manipulate immune responses to fight cancer and other diseases. His approach incorporates signals important for T-cell stimulation in biocompatible polymer particulates, and integrates all the signals needed for efficient T-cell stimulation.

According to the NSF, devices as such these offer ease and flexibility in targeting different types of T-cells, and is expected to lead to state of the art improvements in the preparation of a new generation of therapeutic systems.

 

Molecular Therapy (2008); doi:10.1038/mt.2008.8

Mechanisms of Immunization Against Cancer Using Chimeric Antigens

Manuel E Engelhorn1, José A Guevara-Patiño2, Taha Merghoub1, Cailian Liu1, Cristina R Ferrone3, Gabriele A Rizzuto1, Daniel H Cymerman1, David N Posnett1, Alan N Houghton1 and Jedd D Wolchok1

  1. 1The Swim Across America Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
  2. 2Section of Surgery and Committee on Immunology, University of Chicago, Chicago, Illinois, USA
  3. 3Division of General Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Jedd D Wolchok, Melanoma-Sarcoma Service, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room Z-1462, New York, New York 10021, USA. E-mail: wolchokj@mskcc.org

Received 29 October 2007; Accepted 28 December 2007; Published online 26 February 2008.

Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8+ T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4+ T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines.

Written by huehueteotl

February 27, 2008 at 10:28 am

One Response

Subscribe to comments with RSS.

  1. Please allow me to commend and congratulate Yale University Assistant Professor Tarek Fahmy and graduate student Erin Steenblock for great work towards advancing a simple and understandable approach towards boosting T-cell activity and expansion.
    This research helps open a huge prespective in developing various pseudocell ‘seeds’ that can thence become surface carriers of various biostimulators.
    I hope that the new Global Economical Reform with tax subsidies as ‘ bonuses ‘ and system of rewards could help stimulate important research motivation and advancement beyond the negative forces of market that merely have turned lifesaving perspectives into ‘ hostages ‘ . People could be rewarded when they open new avenues, and this could help underplay previous stumbling blocks, such as stunting positive initiative through excessive corporate greed and ‘squatting’. US educational system helps bring hope towards encouraging and rewarding people of unique backgrounds, histories and efforts, so that good initiatives could be encouraged in future.

    Understanding the molecular biology and biochemistry surrounding all White Blood Cells, and related WBC maturing factors, could help open new doors towards AIDS treatments and possibly also new vaccine strategies.

    MEDICAL BREAKTHROUGH IN HIV AIDSTREATMENT STRATEGY AND APPROACH :
    T-cell quality priming and encoding are assuredly of major importance towards winning over diseases.
    However, very recently, a medical breakthrough in Germany may indicate that the HIV virus is apparently mostly resident in White Blood Cells.

    I could be drawn to this inference by the today published medical result by German doctors who were treating a leukemia patient with a 10-year diagnosed HIV patient.
    After killing off the leukemia patients White Blood Cells, they restituted the White Blood Cells with a bone marrow transplant, and subsequently, they ended up in a patient free of HIV infection.
    I therefore firmly believe that the molecular biology and health of White Blood Cells and possibly other interacting related tissue cells could hold the answer towards attacking the HIV virus.
    During the beginnings of the Mad Cow Disease in Britain, I wrote to the British goverment about the nature of what I called ‘ cryptovirus ‘ that could camouflage itself within macrostructures.
    British researchers called that simplest form a ‘ prion ‘ . HIV DNA has been proven to be amonst the simplest, and therefore can ‘ hitch a ride ‘ on body cells transported throughout the body.

    Today’s sensational discovery in Germany proves to me that HIV infected cells are probably make their host cells more vulnerable.
    By introducing T-cell stimulating pseudocells, a unique avenue is opened, as various T-cells could have different reactions towards those artificial particles.
    In my view, the particles have two major aspects :
    1) The pseudo-cell ‘seed’ which can be ‘ carriers ‘ and can even contain measurable ‘ markers ‘
    2) The surface of the artificial pseudocell can become surface carriers of various substances as your unique research has demonstrated – and thus opening a new avenue towards studying macrofages and various T-cells by contributing towards simple understanding of the structural integrity and health of those T-cells.
    Understanding of various macrophages could further help mark various research study parameters.
    What is quite exciting is that HIV and immunology research has now moved towards understanding how White Blood Cell biochemistry and molecular biology could tell us more as to how T-cell health could be correlated with other White Blood Cells.
    T-cells and Macrophages in general appear to be a most strained category of body cells as they tend to be early collectors of any abnormal cells, and thence becoming the prone carriers of simple DNA strand viruses.
    Systematically marking embuing and marking pseudocells could open a huge chapter in immunology, – specially after today’s German doctors apparent cure of HIV after a treatment for leukemia brings about very exciting perspectives challenging how we could better understand the molecular biology of White Blood Cells in general – and perhaps moving towards understanding the intracellular trigger molecules that help create antigens.
    Perhaps a combination therapy with natural ‘ chemotherapy ‘ substances as Curcumin , combined with PCR exaggerated antigens, could help retrain macrophages towards neutralizing suspicous infected cell fragments, and thence go on to natural adoptosis ( as stinging bees ) once their ‘neutralizing mission’ has been accomplished.
    Combined with simple present anti-HIV drugs such as Neveraprine, HIV could soon become a nightmare of the past, – while demanding that people improve their lifestyles and mindsets, so that all could be allowed to contribute towards thriving economies.

    Your efforts are unique simple procedures that can be understood by other researchers helping towards more direction and purpose , while experts need to review a jungle of past results that too need to be appreciated in their chronological and historical prespectives.
    Congratulations for unique simple advancements that could help towards understanding the subcellular behavior, function, integrity and quality of T-cells and other immunological cells.

    P. Shahir

    November 13, 2008 at 10:39 pm


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: