I've emphasized that the major problem with cancer immunotherapy, in fact with cancer therapy in general, is distinguishing the malignant cells from normals. The CAR-T technique doesn't differ in this regard. As I mentioned in the last post, the two CAR-T constructs that have been approved by the FDA are directed at the C19 cell surface antigen. The reason? It's because the diseases that they're trying to remedy, leukemias and lymphomas, are cancers of B cells, and B cells rather specifically bear CD19 on their surface. But you should see one problem immediately. The treatment will not only kill the cancer, but also normal B cells - cells that are responsible for antibody production.
Actually, this side effect turns out to be one of the less serious reactions to CAR-T therapy, at least in the short term. Patients who received CAR-T cells and who end up lacking antibody producing B cells, can be given immunoglobulins intravenously. However, because the CAR-T cells often persist, and their persistence is correlated with their efficacy, these treatments have to be continued, perhaps for the life of the patient.
A more serious problem, one that has shown up in a large proportion of treated patients, is cytokine release syndrome. Apparently, and especially when the burden of tumor cells is large, CAR-T cells release large quantities of cytokines when they attack and destroy their targets. These cause some serious side effects including fever, nausea, heart problems, kidney difficulties, liver toxicities, and more. It looks like the very success of the CAR-T cells causes these difficulties. Nearly half of the patients in one of the CAR-T trials exhibited the syndrome. Depending on the severity of the cytokine response, there are several remedies available including the administration of monoclonal antibodies against the most potent cytokines.
An unanticipated side effect that shows up after CAR-T treatment is neurotoxicity. Some patients in trials have exhibited a variety of serious neurological symptoms including delirium, muscle spasms, and seizures. Even worse, in one trial, five patients succumbed to cerebral edema – the particular CAR-T treatment used was terminated. No one knows the reason for these effects, although again, some suspect that over-expression of cytokines is responsible.
One limitation of CAR-T therapy that it shares with all other modalities is that cancer cells can escape death by changing the targeted antigen or by masking it so that it isn't detected by the T cell. Some 7 to 25% with acute lymphocytic leukemia patients have experienced relapse via this route after CAR-T treatment. Since cancer cells are continually evolving, any therapy will select for cells that are resistant. Therefore it's important to rid the body of as many cancer cells as possible, the less left behind the better since that makes it less likely that a change in the targeted antigen will occur.
Then there's there's the practical problem of cost. Novartis, the purveyor of one of the two approved CAR-T treatments has announced that a single infusion of CAR-T cells will set patients (or their insurance companies or the government) back $475,000. That's before pretreatment and hospitalization fees, and doesn't include post-treatment follow ups. If you add these costs in, patients will be spending upwards of $550,000. There's some justification for these prices. There's been the extensive developmental costs entailed by drug companies. And recall that the procedure is bespoke – an individual's blood must be drawn; white blood cells purified; CAR's must be inserted into the DNA of the patient's T cells; the transformed T cells must be placed in tissue culture and their number expanded; the cells must be injected back into the patient; and the patient monitored for side effects. Nevertheless, given that close to 175,000 people in the US are expected to be diagnosed with leukemia, lymphoma or myeloma in 2018 (according to the Leukemia and Lyphoma Society of America), these costs will prove a burden to our medical system if CAR-T treatment, as it is now employed, is extensively used. However, current treatments for blood cancers are also very expensive. And they're not as effective. Complex cost-benefit calculations will have to come into play as we employ different modalities of treatments in the future.
The biggest limitation of CAR-T treatment is that while it has proven effective against blood borne tumors, they are only responsible for 6% of cancer deaths. Solid tumors have proved refractory to CAR-T treatment. Many factors seem to be responsible. Again, the choice of which antigen to target is the biggest obstacle. Over the years, more than a half dozen different ones have failed to benefit individuals with a variety of cancers. In several cases, severe toxicity was observed. For example, a clinical trial involving patients with renal carcinoma utilized a CAR directed against a kidney enzyme, carbonic anhydrase, a protein that traverses the cell membrane and is often overexpressed in solid kidney tumors. It was chosen to be a target for CAR-T therapy because it is found in low amounts in normal kidneys and other tissues. However, CAR-T treatment resulted in liver toxicity apparently due to off tumor expression of the enzyme in liver bile ducts. In another case, a patient with colorectal cancer died because of a reaction of the CAR used for his therapy with lung cells. Despite these setbacks, there have been some promising responses in some patients with melanoma and glioblastoma, but in general the results have been disappointing. Why?
Actually, it's not surprising that solid tumors don't respond well to CAR-T therapy. Solid tumors are often surrounded by an extracellular matrix making it hard for T cells to reach malignant cells. What's more solid tumors are often low in oxygen, deficient in nutrients and important amino acids,m and poorly vascularized, creating an environment that makes it difficult for T cells to thrive. Worse, solid tumors produce a variety of inhibitory cytokines that impede T cell proliferation. Finally, CAR-T therapy requires that the cancer displays the target antigen on its cell surface. But most antigens that are tumor specific are expressed within cells. All these difficulties are being addressed by a new generation of CAR-T cells, a topic that I'll take up in the next post.