In the past two decades, much experimentation using gene therapy has been done pre-clinically, and some clinical trials for thoracic malignancies have been performed. In general, these trials have shown safety, but only intermittent efficacy. In vivo gene transfer has been clearly achievable, but with the vectors currently available, it has been very difficult to transduce more than a small percentage of tumor cells, and this is usually only accomplished by local injection. This limitation has thus doomed the approaches that do not have strong bystander effects (i.e. oncogene inactivation or replacement of tumor suppressor genes).
One potential approach that could avoid these problems is secretion of anti-tumor substances such as anti-angiogenic agents. The development of vectors that can induce long term in vivo expression, such as AAVs or lentiviruses, may make this feasible.
However, the primary direction of the field has been a shift toward “immuno-gene therapy”(). This strategy requires only enough gene transduction to stimulate an endogenous immune response and create a strong bystander effect. Promising approaches involve using gene therapy to stimulate anti-tumor responses by a vaccine or by delivering immunostimulatory cytokines. Although these strategies seem to be successful in initiating anti-tumor immunes responses, investigators are beginning to recognize that they are limited by large tumor volumes and significant immuno-inhibitory networks created by the tumors involving cytokines such as TGF-β, interleukin-10, prostaglandin E2, and vascular-endothelial cell growth factor (VEGF) and inhibitor cells such as T-regulatory cells and myeloid derived suppressor cells.84
Future trials are going to likely require combination approaches that stimulate the immune system, reduce tumor burden (surgery and/or chemotherapy) and “inhibit the inhibitors” (with agents such as COX-2 inhibitors or anti-CTLA4 antibodies).
Another major direction of the field is to use adoptive transfer of gene-modified autologous lymphocytes that have been altered ex vivo
by using retroviruses or lentiviruses to augment their ability to attack lung cancer or mesothelioma cells. This can be done by transfection of T-cell receptors with altered specificity or by the introduction of totally artificial chimeric T-cell antigen receptors (CARs) that use single chain antibody fragments to define antigen specificity and intracellular fragments of both the T-cell receptor and accessory molecules (such as CD28 or 4-1BB) to enhance activation.85
A group at Baylor University has begun a clinical trial (see Clinical Trials.gov, identifier NCT00889954) that is targeting HER-2-positive lung cancers with T-cells directed to this antigen that have been modified with a chimeric receptor. These cells are also being modified to be resistant to TGF-β. Our group and a group at Memorial Sloan Kettering Cancer Center are designing CARs to target T-cells to the tumor antigen mesothelin for use in the treatment of MPM. The approach has worked well in preclinical models86
and a clinical trial has been initiated at the University of Pennsylvania.
Gene therapy for lung cancer and MPM has not yet reached clinical practice. An appropriate analogy may be the development of monoclonal antibodies where it took more than 20 years from discovery to actual clinical applications. Despite what some perceive as a slow start, we feel that progress in clearly being made and this therapeutic tool will find its place in the anti-cancer armamentarium in the next decade.