PASADENA, Calif. - The immune system is a remarkable defense mechanism, able to defend the body against a lifetime's worth of pathogens and pathogen attractors--bacteria and viruses, toxins and parasites, splinters and cuts--everything, that is, except cancer. Although the immune system handles most of these disease-causing organisms and insults well, it does a poor job of suppressing the growth of tumors.
A major goal of cancer immunotherapy has been to bolster the immune system by generating large numbers of white blood cells (T cells) that could specifically seek and destroy cancer cells. Now, two scientists from the California Institute of Technology have come up with a novel and promising approach to antitumor immunotherapy. Reporting in the online edition of the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), Lili Yang, a postdoctoral scholar, and David Baltimore, professor of biology, Caltech president, and Nobel Prize recipient, have developed a new methodology they are calling "instructive immunotherapy" that someday may fight human cancer.
In mice and humans, hematopoietic stem cells (HSC) form both red blood cells and immune system cells. In mice, Yang and Baltimore succeeded in altering some HSCs so that they would generate specific kinds of T cells that aggressively attack and destroy specific cancer cells. Once the mouse immune system received this enhancement, it became able to generate its own cancer-specific T cells on a long-term basis. When helped by dendritic cells (another type of immune system cell) carrying a piece of the tumor's marker protein, the methodology achieved the complete elimination of large, established tumors. While the work is preliminary and was done with mice, says Baltimore, instructive immunotherapy could eventually be used for controlling the growth of tumors in humans.
"We've achieved something that could one day prove important," says Baltimore, who was awarded the 1975 Nobel Prize in Physiology or Medicine, "but the first caveat is that this is all with mice, and mice are often not predictive of behavior in humans." Still, he notes, "everything we have done is in principle possible to do in humans, so we plan to try to develop a system for optimizing the ability to program human stem cells."
Yang, a former graduate student of Dr. Baltimore, says current cancer strategies fall into two categories: developing a cancer vaccine, or developing a drug that can be given when cancer is diagnosed. "Our strategy is threefold," she says, "a combination of gene therapy, stem cell therapy, and immunotherapy. When these three methodologies work together, it is possible to provide life-long immunity."
In addition to making billions of new blood cells each day, HSCs are responsible for providing immune protection of every cell type in the body. In fact, HSC transplants are routinely used to treat patients with cancers. In their case, Yang and Baltimore chose to manipulate HSCs for three reasons--because HSCs normally make T cells, they make them by the billions, and they exist in humans through their lifetime.
The first step was to design a retrovirus vector that could deliver genes for both chains of the T cell receptor to HSCs. This was actually the key to the whole study. For this work, two vectors delivering two sets of genes were developed. The HSCs then gave rise to both of the major types of T cells known as CD4 helper cells and CD8 killer cells. Together, these two cell types can recognize the foreign nature of the test cancer cells used in the study and can kill them. The researchers were successful in programming up to a quarter of the mouse's T cells to react to the model tumor. Even better, once modified, the mouse's immune system continued to produce these antigen-specific T cells on its own. However, with this method alone, Yang and Baltimore found that mice were only partially resistant to the tumor cells.
To achieve complete protection required boosting the animal's immune system with dendritic cells carrying a fragment of the tumor cell's marker protein. These dendritic cells are thought to use their long tentacle-like branches (called dendrites) to stimulate the T cells and make them more active. With this combination, Yang and Baltimore were able to achieve the complete shrinkage and suppression of even large, well-established tumors.
Dr. Yang recalled her reaction to the first positive results: "It was a great surprise that the method worked so well. This level of efficacy makes us believe that the method may have real therapeutic potential."
The next step, says Yang, will be to repeat the experiment, this time using conditions that more closely approximate human tumors. After that, if things hold up, the next step will be to start thinking about human trials.
"Producing a state of antitumor immunity has been a dream of immunologists for years, but has been unrealized in humans," says Baltimore. "Here we've developed a methodology that provides a new opportunity to realize this goal. We certainly hope that it will prove to be effective in humans."
