In the last few weeks I've gotten a chance to read a half dozen papers that describe novel and ingenious potential cancer immunotherapies. They've all been worthy of a post. However, just the other day, on Wednesday, January 23, I was introduced to a new approach to cancer therapy via a different route – an internet seminar, a "webinar". Hosted by the American Association for the Advancement of Science (AAAS), it was entitled "Cell and Gene Therapies for Cancer:Future Promises an Challenges". It was instructive to hear a presentation in this format because I had never attended a webinar previously. The format didn't allow me to actually see the speakers, but their slides were shown and I could hear their presentations. Overall, it was a splendid experience and I found it exciting to hear research scientists speak directly about their work.
There were two presentations each a half hour long, but I'll only discuss the second one, offered by Dr. Lawrence Cooper, previously a professor and section chief of cell therapy at the MD Anderson Cancer Center in Houston. He left his position there to become, in 2015, the CEO of Ziopharm, a biotech company. Cooper is taking an innovative approach to immunotherapy, making use of engineered T cell receptors, rather than CAR's. Here's some of what I learned from his stimulating presentation.
Disadvantages of CAR's
Chimeric antigen receptor - T cells (and natural killers) have had remarkable success in the last decade or so in treating some cancers of the blood. But they've not been as successful in combating solid tumors. Cooper cites several reasons, some of which I've discussed in previous posts. One major problem that CAR's face is that they're engineered to target a specific antigen that sits on the surface of a cancer cell. Cooper calls these antigens "germinal" or "shared" or "public", meaning that they're common to both normal and tumor cells. When CAR T's directed at these antigens are deployed, they therefore attack normal as well as cancer cells. For example, when CAR T's were used as immunotherapy for leukemia, both the leukemic cells and normal B cells were killed. It was possible to ameliorate this problem by giving patients external antibodies, but that's not a general solution for other kinds of cancer. One way of getting around this problem is to target CAR T's against cancer specific public antigens (antigens found only on, or almost only on, tumors), but these have been difficult to identify (assuming that they exist at all). One reason? The antigens must be on the surface of cells in order for the CAR to bind to it. And surface proteins only represent a small fraction of the potential antigens that might be useful in distinguishing cancer cells from normals.
Killer T cells can "see" proteins inside of cells by making use of their receptors and the MHC. That might expose more candidates for therapy, but Cooper makes note of am associated problem of which I wasn't aware. It appears that the T cell response to a shared antigen is generally weak, presumably because the mechanisms that prevent autoimmunity lessen their potency. For this reason, Cooper envisions the cancer immunity field turning to neoantigens as targets. Neoantigens arise by mutations in the genetic material that often result in proteins that carry amino acid differences with respect to normal cells. These differences can result in proteins that appear foreign to the immune system and are therefore potentially immunogenic and capable of being detected by T cell receptors. Using such neoantigens should decrease the likelihood that a patient's T cells will react with normal cells, thereby increasing the chances that their response will be more potent. But focusing therapy on neoantigens has many challenges. For one, therapy must be individualized because every tumor will likely harbor a different population of neoantigens. Second, many tumors will be heterogeneous, some sectors will undoubtedly bear neoantigens that are different from others. Such tumor heterogeneity will increase the chances that the tumor will regrow even after an initial positive response. Therefore, cancers may have to target multiple T cells bearing a variety of receptors. Third, and perhaps most important, is the problem of how to detect the neoantigens in tumors. It's all very well to say that neoantigens make good objectives for therapy, but how does one find them and then create T cells that seek them out?
New DNA sequencing techniques have made it possible to find mutations in tumor cell populations. In particular, so-called whole exome sequencing, where scientists determine the DNA sequence of exons, the expressed portion of the genome that represent less than 2% of the entire DNA, can be done relatively cheaply. By comparing a tumor's DNA sequence to that of a normal cells, differences may indicate mutations and potential neoantigens (step 2 in the figure). In turn, it is possible to synthesize these protein fragments (step 3), transfer them into dendritic cells (step 4), have the dendritic cells display protein fragments (peptides) on their surfaces, and to select T cells from a tumor that specifically bind to them (steps 1a and 5). The result is a population of T cells that is dedicated to seeking out tumor cells bearing specific mutated genes that can be expanded and transferred back into the patient.
This sophisticated, multistep approach seems to have been successful in several cases in the last few years, and has achieved particularly dramatic results recently. A 2018 paper in Nature Medicine describes how a patient with advanced metastatic breast cancer who had not responded to prior therapy was found to be cancer free 42 weeks after this mode of therapy. Her numerous liver and subcutaneous metastases had regressed completely. The results from this study demonstrate that this basic approach works; that they're a proof of principle. That's the good news. The bad news, from a practical point of view, is that the procedure is not scalable. And, because in trials not all patients have responded favorably from the treatment, its potency might also be improved. It's these two aspects of the treatment that Cooper addressed in his talk.
An Improved Procedure
Cooper notes that a large number of laboratories have developed methods for detecting neoantigens. As described above, exons from tumor fragments are typically sequenced and compared with DNA extracted from non-cancerous tissue in the same patient. The suspected neoantigen peptides are tested against the patients own T cells. In what Cooper considers a less effective technique, those T cells that recognize these neoantigens are amplified in culture and used for therapy. Cooper favor an improved approach, where the DNA that specifies the T cell receptors from reactive T cells is transferred into naive T cells. That is, a population of T cells from outside the tumor is engineered to produce a T cell receptor that will react with the tumor neoantigen. The idea is that these engineered naive cells will be more potent than the progeny of the T cells that have already infiltrated the tumor.
This technique borrows from the CAR world. But instead of creating a new engineered B cell receptor for a T cell, the approach that Cooper describes puts a modified T cell receptor in place of a natural one. Cooper devotes most of the last third of his seminar to improvements in how this last step, a gene transfer, is achieved. I won't go into this part of his talk, except to say that the techniques he describes are much more efficient than the procedures that are usually employed. They offer the prospect of a far less expensive and perhaps even commercially viable treatment in the future, one that is applicable to many more patients. We'll see. According to Cooper, clinical trials will begin this year.