CAR-T Immunotherapy

CAR-T immunotherapy has a reputation for being the new exciting thing in cancer, and as far as I can tell, this reputation is mostly deserved.

It’s not a single therapy, but a general technique. You graft the monoclonal antibody of your choice onto a T-cell with retroviral vectors; then it can selectively attack any type of cell that has a distinctive antigen.

An advantage of CAR-T cells is that the chimeric antigen receptor need not depend on HLA, so it can overcome the tumor’s ability to downregulate HLA molecules.  CAR-T cells bind directly to the antigen, usually on the surface of the cell.

Early clinical trials have shown really strong responses to CAR-T therapy in leukemia and lymphoma.

CAR-T caused complete remission in two children with refractory acute lymphoblastic leukemia; one relapsed after two months and one remission was ongoing.  (ALL is curable in 80% of children, but prognosis is poor for those with chemotherapy-resistant disease.) The cells were modified with specificity for CD19, a hallmark of B-cells.

LeY-specific CAR-T cells in relapsed acute myeloid leukemia (AML) caused a (temporary) remission in 1 of 4 patients.

CD-19 specific CAR-T cells produced an 88% complete response rate out of 16 patients with relapsed acute lymphoblastic leukemia; there were 10 complete remissions.

5 out of 5 adult patients with relapsed ALL treated with CD19-specific CAR-T cells had complete remissions.

3 out of 11 patients with high-risk neuroblastoma had complete remissions upon treatment with EBV-specific and GD2-specific CAR-T cells.

Of 3 patients with relapsed indolent B-cell lymphoma treated with CD20-specific CAR-T cells, 2 survived progression-free for 12 and 24 months, and 1 had a partial remission and relapsed after 12 months.

Leukemia and lymphoma are “easy mode” for a few reasons. First of all, several types of such cancers have very specific biomarkers. The Philadelphia chromosome  is pretty much unique to the leukemias on which it exists. B-cell lymphoma is restricted to B-cells, and CD19 and CD20 are markers that occur on almost all B-cells and no other cells.  The common solid-tumor cancers (lung, breast, colon, prostate, etc) have no equivalently specific markers. Second of all, blood cancers are easier for drugs to physically access than solid tumors, which produce a hostile “microenvironment” that protects the tumor against attack, especially immune attack.

Challenges facing CAR-T therapy include the cost of engineering T-cells, and poor in-vivo persistence of transferred T-cells.  Second- and third-generation CAR-T therapies involve editing multiple stimulatory domains, since using only one often fails.  Exogenous cytokine administration, especially IL-2, is used to enhance persistence of T-cells.  A challenge especially for solid tumors is transferring T-cells to the site of disease, and resisting the immune-suppressive effects of the tumor microenvironment.  Fever enhances the adherence of T-cells to the tumor microvasculature, so heat therapy may be helpful here.  (Note that fever is also a factor in spontaneous remissions and bacterial cancer therapies.)

Attempts so far in solid tumors include CAR-T cells specific for HER2, VEGF, EGFR, and GD2.  So far, it doesn’t work most of the time, though the GD2 studies in neuroblastoma got some complete remissions. The HER2-sensitive trial caused one death due to the T-cells attacking healthy tissue and causing respiratory failure. Lack of specificity and lack of persistence have been problems, but as of 2015 we’re still waiting for the results of many solid-tumor clinical studies.

CAR-T is “decisive” in some types of leukemia and lymphoma; complete remissions in a majority of patients is a nearly-unheard-of result in the world of cancer. It’s not particularly “simple”, because it can be customized arbitrarily with different antigens, different activating domains, etc.  It’s also only somewhat “upstream” — T-cells appear fairly late in the process of immune response to cancer.

Ultimately, though, CAR-T is only as good as the specificity of the cell surface antigens it uses.  It’s subject to the universal challenge of targeted cancer drugs: different cancers have different biomarkers, no one biomarker appears in a majority of cancers, and cancers change their biomarkers as they advance.

If anti-IgG pans out as a much broader cancer-detection mechanism, it seems that it could in principle be applicable to CAR-T.  Also, combination CAR-T with multiple antigens pattern-matches to something that could improve effectiveness.

CAR-T is not an underappreciated area of research — it’s very actively funded and a vigorous research field.  To the extent that it pans out, which will become clearer when the current round of clinical trials publish results, it’s evidence for the “cancer establishment” doing something right, very much as imatinib was a triumph of “big science” and targeted chemotherapy.

The cynical viewpoint is that, like imatinib and targeted chemotherapies, a single clear-cut triumph can lend credibility to a wide class of drugs that mostly don’t work on more difficult cancers, and that since CAR-T is so mutable, it is especially vulnerable to such “exploitation.”  One way or another, we’ll find out when the solid tumor results finish coming in.