14 Nov 2012
Tumor Specific T cells with improved efficacy; Expert thank new age genetic engineering tools
Cancer Immunotherapy is one of the recent successful approaches in the treatment of cancer. This concept has evolved on the principle that a competent immune system can prevent the spread and growth of tumors very effectively than any other therapeutics. The earlier days of this concept’s inception didn’t see any promising practical results but over the years there has been a tremendous improvement in the approach and results as well. Many of the therapeutics evolved through this concept are already in clinical use today.
Cancer Immunotherapy can be achieved with three different approaches namely Passive immunization, Active Immunization and Immunostimulation; however immunostimulation is used to augment the effects of former approaches than the individual therapy.
Monoclonal Antibodies (mAbs) which specifically target an antigen or a receptor site on the tumor cells and destroy them are the candidates of passive immunization. FDA approvedRituximab of IDEC Pharmaceuticals, Ofatumumab of Genmab A/S and GSK and Roche’sBevacizumab have capitalized on the cancer therapy market in the recent past and have defined the potential of cancer immunotherapy. Despite this fact mAbs couldn’t evolve as the magical bullets breaking all cancer barriers because of several limitations. mAbs are very specific to their targets hence they fail to recognize the smallest mutations which alter the target sites and toxicity is one of the significant worries when mAbs are administered in high doses.
Cancer Vaccines similar in context to the traditional vaccines are targeted against specific proteins of tumor cells and immunize patients against them. Many of the pharmaceuticals have put in their expertise to come up with a potential candidate but Antigenics’s Oncophageand Denderon’s Provenge are the only approved therapies till date. This filed is yet under infancy and faces very similar limitations as that of mAbs; cost and lack of efficacy being the major ones. Global efforts were also put on activating subject’s immune cells ex vivo using adoptive cellular therapy. But severe hypersensitive reactions and low scalability hindered further progress. Fortunately the newer genetic engineering methods have made researchers to overcome these limitations and redirect this method with more specificity and efficacy.
T lymphocytes which are known for their better cytotoxic effects towards the tumor cells have been identified as the best candidates to effectively perform the tumor specific cellular therapy. To define in a line; tumor specific cellular therapy genetically modifies the T cells to render them specificity towards tumor cell antigen and hence perform cytotoxicity towards cells bearing that antigen. The study conducted by Dr. David L. Porter, Director, Blood and Marrow Transplantation at Abramson Cancer Center and others redefined this decade old method as follows and have witnessed high value results portraying the hidden ability of cellular therapy [1]. Before reading through the study it is good to know some key factors utilized;
Chimeric Antigen Receptors are genetically engineered receptors which can be used to confer specificity to immune cells (T cells) towards particular antigen. The genetic sequences of these CARs can be transferred to a T cell in vivo or in vitro through new age tools like retrovirus vectors. Hence this process can yield numerous tumor specific T cell warriors.
T cell co-stimulators play prominent role in completing the T cell activation cycle. These immune molecules interact with the co-stimulatory molecules expressed on the antigen presenting cells (APC).
T cell receptor signal transduction molecule is one other important factor which couples the antigen recognition to several other intracellular signal-transduction pathways. Low expression of this molecule would generally lead to inadequate immune response.
So the study group designed a lentiviral vector (sub class of retroviruses) expressing the chimeric antigen receptor specific for the B-cell antigen CD19, as CD19 is expressed on most of the B cell malignancies. It also coupled a T cell co-stimulator CD137 molecule inducing co-stimulation to the activated T cells and a CD3 zeta signal transduction molecule to enhance the immune response. After transducing human cells with this expression system and expanding them ex vivo, a very low dose of transduced T cells was infused into patients with refractory Chronic Lymphocytic Leukemia. The modified T cells were found to be increased by more than 1000 times the initial infusion and more importantly these cells persisted at high levels for more than 6 months leading to a very good remission period. There were some minor off target side effects which can be reduced with preventive measures.[2]
With increasing count of cancer victims every day around the globe there is an evident need for a generalized therapy, otherwise subjects would have to opt the existing therapies which themselves cause number of adverse effects. Hence global efforts are now redefining the concepts like cellular immunotherapy with application of new age genetic methods. The results coming out of this approach are really impressive and the medical community is happy about this remarkable progress but it also says bringing this simple concept into practice will not really be a cake walk.
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