A new approach to fighting cancer

The body’s immune system is a remarkable defense mechanism, able to beat back a lifetime’s worth of bacteria and viruses, toxins and parasites—everything, that is, except cancer. Although the immune system handles most disease-causing organisms well, it does a poor job of suppressing the growth of cancerous tumors.

Now, two Caltech scientists have come up with a novel and promising approach to fighting cancer. Lili Yang, a postdoctoral scholar, and David Baltimore, president of Caltech, professor of biology, 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 of these HSCs to make them generate specific kinds of immune system cells, called T cells, that aggressively attack and destroy specific cancer cells.

Once the mouse immune system received this enhancement, it was then able to generate its own cancer-specific T cells on a long-term basis. And, when helped by another type of immune system cell, the methodology proved to be even more powerful, achieving 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.”

In addition to making billions of new blood cells each day, HSCs are responsible for providing immune protection for every cell 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 virus, normally an infectious agent, that instead would serve as a delivery vehicle to get the T-cell genes to the HSCs. This was actually the key to the whole study. The HSCs then gave rise to two 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 cancer cells used in the study and 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 the mouse’s immune system was modified, it continued to produce the 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 another type of immune cell called a dendritic cell. These 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.

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.”
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