The FDA’s first ever approval of Kymriah, a CAR-T drug for acute childhood leukaemia, was a milestone for immuno-oncology and has justifiably hit the headlines. But it is far from the end of the story, as a long study from Dr John Savin and Dr Daniel Wilkinson of Edison Research makes clear.
This research paper also has important conclusions for investors, which I will come to in a moment. But it also positions CAR-T within the bigger picture of cancer immunotherapy and explains the strengths and weaknesses of the various competing approaches.
To remind you, immunotherapy simply means that we are using the body’s own immune system to tackle disease and cancer is the big immediate target. T cells are the foot soldiers of the immune system. They roam around the body looking for viruses, bacteria and damaged cells and then kick off a process that destroys them. While this works well with invaders from the outside, cancer is a more difficult enemy precisely because cancer cells are not foreign invaders but are ‘self cells’ that have started to misbehave.
Cancer immunotherapy aims to boost the immune system, better enabling T cells to recognize cancer cells and destroy them. You can think of cancer cells as tiny white tennis balls and T cells as tiny yellow tennis balls. Each little thread of fluff on the surface of the yellow balls can dock on to a particular thread on a white ball. So if all the balls are mixed in a big bag and shaken about some of the yellow balls will cling to some of the white balls. In the body the T cell tennis balls will then destroy the cancer tennis balls.
Crucial to the process is the initial recognition. If the T cells can attach themselves to the cancer cells then the immune system will do the rest. The main dangers are toxicity, when the T cells also dock on to and destroy healthy cells, and potentially fatal ‘cytokine storm’ as the fragments of the destroyed cells overwhelm the body’s ability to clear them.
Edison describes five different approaches to cancer immunotherapy. The first two, CAR-T and TCR both require the engineering of T cells.
CAR-T (Chimeric Antigen Receptor) : T cells are taken from the patient and engineered to express a feature on their surface that will recognize and dock on to a specific feature on the surface of the cancer cells (the usual target is the protein CD19). This feature is called a single chain variable fragment and is derived from the portion of an antibody that specifically recognizes the target CD19 protein. CAR-T therapies need prior chemotherapy, which adds cost, toxicity and risk. While the CD19 protein is the leading antigen target it is also found on healthy B-cells which suffer collateral destruction leaving the patient requiring supplemental injections.
TCR (T Cell Receptor): This is very similar to CAR-T except that the T cells are engineered to recognize tumour-specific proteins that occur not on the surface of cancer cells but within them. These then show up on the surface of the cancer cell in the company of another protein called major histocompatibility complex. These surface markers cannot be recognized by the CAR T approach. TCR trials are at an earlier stage than CAR-T but the approach offers high selectivity, meaning that the engineered cells will only engage with the target cancer cells. Thus they will spare healthy cells, but on the other hand will not kill any cancer cells that are not expressing the target protein.
BiTEs (bispecific T-Cell Engagers): These are monoclonal antibodies in the form of a double-headed spanner. One end is engineered to dock on to a cancer cell and the other is engineered to dock on to a T-Cell. When infused into the body they link the T cell to the cancer cell, bringing them together. These are relatively large molecules and thus have difficulty penetrating solid tumours.
Checkpoint Inhibitors: Cancer cells will often display upon their surface protein markers that are typical of healthy cells. If T cells dock on to and recognize these ‘normal’ markers they will not kill the cancer cells. Checkpoint inhibitors are like blindfolds, placed upon either the T cell surface marker or that of the cancer cell so that this recognition will not happen. This leaves the T cell free to kill the cancer cell. Examples of approved Checkpoint Inhibitor drugs are Keytruda, Opdivo, Tecentriq, Bavencio and Imfinzi. These are effective against cancer but can unleash the immune system onto healthy cells and cause potentially serious side effects.
NKR CAR (Natural Killer CAR): A relatively new approach, pioneered by the Belgian company Celyad, identifies NKG2D ligands. These are cell surface proteins that present only at low levels on the surface of normal cells but are overexpressed by damaged cells. This is a theoretically promising approach but we need to see clinical evidence of efficacy.
This represents the current toolbox of cancer immunotherapy and some such drugs, including the Kymriah CAR-T therapy, have been shown to extend the lives of patients and thus received approval. But before we can say that we have beaten cancer we still have mountains to climb.
First we don’t know how long these cures will last. While patients may appear to be in complete remission from cancer it is unlikely that every cancerous cell in their body has been eliminated. One day it may reappear. Meanwhile the immunotherapies themselves consist of live cells. As these die the impact of the therapy may wear off. While there are now many cases of patients in remission from cancer thanks to immunotherapy, for how long only time will tell.
The biggest research challenge is to extend the benefits of immunotherapy to solid tumours. So far we have only achieved success against ‘liquid’ tumours, and only a sub-set of those. According to Edison CAR-T therapies have only been successful against Acute Lymphoid Leukemia and Diffuse Large B-cell Lymphoma. It may help to ‘precondition’ patients, for instance by administering radiotherapy or chemotherapy before unleashing an enhanced immune response. It may also help to combine known treatments, such as CAR therapies with checkpoint inhibitors.
But solid tumours present particular challenges. First there is so far a lack of known antigen targets – surface markers such as CD19 that can distinguish cancer tumour cells. Next we have to find effective ways of getting the immunotherapy drugs to the site (or sites) of the tumour. And finally the drugs have to overcome an immunosuppressive micro-environment – meaning that immediate surroundings of the tumour cells are hostile to attacks by the immune system.
This is highly complex and for the time being most of the research dollars are being aimed at the easier targets. As researchers target liquid cancers 53% of the clinical projects target less than 10% of the patient market. While many companies and research institutions no doubt intend to take the lessons learned from tackling liquid cancer into solid cancers the fact today is that a large number of competitors have their eye on a relatively small prize. ‘As the haematology CAR market matures,’ says Edison, ‘there may be several companies chasing a relatively small pool of eligible, funded patients.’
Even assuming that CAR-T and TCR therapy is shown to work the other major obstacle is its cost. Extracting cells from the patient, re-engineering and multiplying them in the laboratory and then implanting them back into the patient takes up to a month and involves manual procedures. A cheaper alternative would be to use allogeneic cells taken from third parties and stored ready for use, but a trial of engineered allogeneic cells run by Cellectis was stopped in September after one trial patient died.
So the promised land is still some way distant. Edison calculates that 1.3m patients a year, in the USA alone, with solid tumours could benefit from immunotherapy. ‘T-cell therapies could have a major impact on many solid tumours if they are effective, if they can be made in quantity and if volume production makes them more affordable.’ Those are three big ‘ifs’. But Edison’s conclusions do underscore the investment strategy of the Breakthrough Biotech Alert – which is to treat the drug developers with extreme caution, but to favour companies supplying the picks and shovels to the massive and important global research effort to beat cancer.