Now for the High-Hanging Fruit
We should be thrilled with the success of the approved CD-19 CAR-T therapies. But the field is still young, and we are only scratching the surface of what’s possible.
Miguel Forte | | Opinion
Recent approvals from both regulatory agencies and health technology assessment bodies are showing that cell and gene therapies can be commercially successful. And though it’s right to be delighted that these fantastic technologies are beginning to treat and, in some cases, cure patients with life-threatening diseases, we should also recognize that the field is still in its infancy.
We are only just beginning to see the fruits of years’ of investigation into understanding the role of lymphocytes in controlling cancer – going all the way back to tumor-infiltrating lymphocytes. The question for the field has been how we can harness and direct the immune system to fight cancer. The field has shown that it is possible to put a chimeric antigen receptor (CAR) on a T-cell, have it recognize an antigen on the cancer cell and activate the intercellular machinery. CD19 is the target for both of the products on the market today and is really the core of the cell therapy field. The fact that it is only expressed in B-cells allows us to specially target cancers arising from this type of cell – such as B-cell lymphomas, acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
In other words, the CD19 antigen is the low-hanging fruit. Now, we must find ways of targeting other cancers – especially solid tumors. There is a lot of interesting work going on in terms of addressing the tumor microenvironment, including the ability of the cells to penetrate, and the ability of cells to act and work near tumors. But above all, choosing the right targets within the tumor cells will be key. And finding tumor-specific targets isn’t easy – especially for solid tumors. Here, creating more elaborate CARs – combined CARs, modulated CARs – will be important. We’re no longer just targeting; we’re fine-tuning the targeting mechanisms.
Some academic centers and companies are developing CAR-Ts with two simultaneous chimeric receptors like CD19 and CD22. This dual targeting could improve efficacy and also prevent some cases of resistance. On the other side, the functionality of the CAR-T cells can be amplified with simultaneous expression of the CAR and cytokines, or via a modulable T cell activity, allowing for T cells to be eliminated in case of side effects.
A promising alternative to CAR-T cell therapy is TCR (t-cell receptor) therapy. Unlike CAR-T cells that recognize proteins expressed on the surface, T cell receptors (TCRs) can recognize tumor-specific proteins on the inside of cells. When tumor-specific proteins are broken into fragments, they show up on the cell surface with another protein called major histocompatibility complex (MHC). TCRs are engineered to recognize a tumor-specific protein fragment/MHC combination. A CAR is very much a jump key that recognizes the antigen on the surface, whereas a TCR has a lot more finesse in terms of how it recognizes the antigen.
The main advantage of TCR cell therapy is the breadth of antigens that can be targeted. Around 10 percent of antigens can be targeted by CARs, whereas TCRs have the potential to target all antigens. And this may allow TCR cell therapy to crack solid tumors. Some success in solid cancers has already been documented with engineered MHC class I TCRs, namely with the NY-ESO antigen. Research and development is ongoing with some promising new approaches like TCRs from immunized long term survival patients or MHC class II TCRs that could potentially provide a broader mechanism of action, and which may be relevant in the context of targeting solid tumours.
That being said, I see TCRs and CARs being worked on in parallel. We have a great deal of experience using CARs and they still have great potential to treat cancers outside of B-cell cancers. Some cancers will be treated with CARs and others with TCRs. But what’s really exciting is that we’ve only just scratched the surface of what we can achieve with cell and gene cancer therapies. It’s time for the field to build on our successes of grabbing the low-hanging fruit and move onto more difficult and widespread cancers.