In 1890 the German physician Paul Erlich began immunologic research in Berlin ( later in Frankfurt ), at the Institute of Experimental Therapy. He did so at the entreaty of Dr. Robert Koch. The hope was that they would be able to ascertain the mechanisms by which innate immunity could be enhanced in such a way that it would be an effective treatment for both infectious and neoplastic diseases. At the time they possessed neither the knowledge, nor the technology to make this approach a reality. Nevertheless, a century on, the situation has improved considerably. The latest success in early clinical studies has taken a novel approach by using genetically modified T cells. Most of the initial research has been done at the NCI and University of Pennsylvania in the setting of advanced lymphoid neoplasms.
The procedure involves removing T cells from individual patients after which they are bioengineered. The lymphocytes are then genetically modified so as to express an anti-CD 19 chimeric antigen receptor which enables the cells to specifically target the B cell antigen CD 19 which is present on many lymphoid malignancies. After infusion back to the patient, they bind to tumor cells and simultaneously undergo expansion and rapid proliferation. The antitumor activity persists for many months.
Out of one group of 13 patients with advanced diffuse large B cell lymphoma, primary mediastinal lymphoma and chronic lymphocytic leukemia, there were 5 partial and 7 complete responses. The primary toxicity consisted of acute cytokine release syndrome and activation of macrophages which induced high fevers, hypotension, and dyspnea. Interestingly, the effects of the cytokine cascade responded well to infusions of the anti-Interleukin-6 monoclonal antibody Tocilizumab.
The results of 2 additional trials with a total of 32 CLL patients have reported 15 partial and 7 complete responses. Similar outcomes have been seen in adults and children with B cell ALL. The use of chimeric antigen receptor T cells (CART therapy), albeit experimental, leads to several conclusions which are compelling and provocative. One significant finding is the realization that it is indeed possible to eradicate large volume tumors using an “all biological approach.” Moreover, the toxicity, though pronounced, is both reversible and short-lived. Several patients with malignant lymphoma and CLL who have received CART therapy have remained disease-free for close to 4 years. These results are in contrast to the unrefined and nonspecific immunotherapy that was attempted during the 1970’s. After the failure of those trials, it was felt that immune-based treatment for malignancy was unlikely to ever be a realistic option. Consequently, a myriad of aggressive, high-dose chemotherapy/bone marrow transplant protocols were designed and came to be regarded as the most promising treatment for advanced, refractory malignancies. Ultimately, this proved not to be the case and yet ,owing to remarkable advances in genetic engineering and development of monoclonal antibody therapy during the past 2 decades, the immunologic approach favored by Dr. Ehrlich has finally become possible.
Clinical research with the new adoptive T cell method is ongoing and given the promising results achieved thus far, optimism is justified. Furthermore, the results suggest that over the next few years biological therapies will increasingly be on the ascendant, while concurrently, the older cytotoxic chemotherapy based programs will follow a similar but inverse path.
Dr. Carter is an oncologist who has practiced in Tennessee for more than two decades. He joined The Family Cancer Center in the fall of 2009.
