Era of Hope 2011 Investigator Vignette

Title: Designer T Cell Gene Therapy to Eradicate Metastatic Breast Caner

Investigator: Richard Paul Junghans, PhD, MD; Roger Williams Medical Center/Boston University School of Medicine

I believe in the power of the immune system. When turned inward such as in lupus and rheumatoid arthritis and so forth it can—it can destroy people, it can damage them, it can—and what we need to do is take this—this sword and direct it in the—the way we want it. There is incredible power of the immune system specifically T cells to fight viruses. I believe firmly that we can do that to fight cancer as well and we can be just as effective as we try out new things and get better at imitating or understanding how the immune system does it.

What we do is we genetically engineer a patient’s own T cells. They come into the clinic. We use leukapheresis machine, which is something like a dialysis machine, and remove white blood cells from the blood and return the red blood cells. And then we take the white blood cell product to the lab, and over a period of about a month we modify these cells so that they now have a new specificity. So we teach these T cells to attack the cancer, basically hijacking the antiviral mechanisms of the T cells to be anti-cancer.

So this is the engine, the recognition system, and the motor which allows T cells to see a virus infected cell or to see a tumor cell and attack it and kill it. We take an antibody to a protein that’s on the surface of a tumor cell, in this case would be CEA, which is common on breast cancer cells, and then we graft it onto the zeta chain of the T-cell receptor, and this gives it a new specificity so that it isn't just attacking a virus anymore but it’s attacking the cancer.

So CEA is big not just in breast cancer but in lung cancer, colon cancer, medullary thyroid cancer; there’s a number of cancers that it’s expressed on. So the principles developed here they could actually apply more broadly.

We make this chimeric molecule we call it and we put it into this retroviral vector and it takes DNA into the infected cell and genetically modifies itself. So this T cell that gets this retroviral vector now permanently expresses this new protein, which is the new receptor, also called CAR for chimeric antigen receptor. And we can detect the presence of this gene expressed in T cells. Here we have green cells here, which are all T cells, and these two with the red dots on them. Those red dots are the new genes that are being made that—that make these able to attack the cancer cells.

What we’ve done differently with this product now is that we’ve added some new signals to the designer T cells. So as they originally built, we had one signal once this antibody bound to the tumor cell, and that’s good enough for killing but it turns out that you need two signals to keep the T cells so that they are multiplying in response to contact with virus or with—or with tumor.

We figured out that first generation designer T cells that just have this recognition domain, Signal 1, they will kill but then they die off. They will kill several tumor cells and then they get exhausted and die off. So what we wanted to do is do what the normal immune system does in fighting a virus infection. So there are cells called antigen presenting cells that present a viral antigen to the T cells, give it in Signal 1 like we’ve engineered but there’s a second signal called Signal 2. B7 is on antigen presenting; CD28 is on T cells. And that gives Signal 2 so antigen presenting cells are expert at making us recognize viruses. But tumor cells don’t have B7 so we only got Signal 1 and not Signal 1 plus two. And the T cells would die from activation and do cell deaths because we didn't have enough signals.

And so we put CD28 into this so that we get Signal 1 plus two instead of just Signal 1, and we look at what happens to the T cells when they’re put on tumor cells. So if the T cells are unmodified and they’ve just been activated prior to putting in with the tumor cells, they just grow unaffected. The first generation grows and then are dying off. And the second generation not only do they not die off, they actually increase in their numbers, so they start proliferating massively. So that was the whole basis for this new generation, second generation of designer T cells.

So the grant itself funds the clinical trial with our most current advanced agent. It also funds future research to do further pilot clinical trials with patients to prove these other hypotheses of action by which the T cells can be improved and also to create new generations of desired T cells which have further functions. So these are not like your grandfather’s drugs. These are new agents. These are alive. These are not inert chemicals or even biological molecules. These are living organisms that we have retuned and trained. I like to call them little nanobiobots but you know it isn’t something that’s really going to catch on I don’t think as a term but it really captures the idea that we are doing engineering and making these cells to function in the way that we want them to. And we’re learning as we go.