Cancer immunotherapy, named Science’s “breakthrough of the year” 2013, is the manipulation of the patient’s own immune system to combat a disease. Since its initial beginnings in the late 1980s cancer immunotherapy has grown to be one of the most exciting prospects in biomedical science today. The first treatment of this type came in the form of an antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), a protein on T cells that is known to reduce the T cell response when active. Blocking this function with an antibody it was hypothesized, by immunologist James Allison, may enhance the immune response and let it properly attack cancerous cells, as the researchers then demonstrated in mice. This idea was developed by a small biotech,Medarex, which was then bought by Bristol-Myers Squibb. It wasn’t until 2010 that the company could report that their antibody had increased the life-span of patients with metastatic melanoma from 6 months to 10 months, the first treatment shown to extend life in this form of cancer trial.
Another aspect of immunotherapy, aside from antibodies and other biologics, is the manipulation of T cells directly harvested from the patient to be active cancer hunters when re-administered. This work, a form of cellular therapy, was pioneered by Steven Rosenberg and has been followed up on by a multitude of researchers, commonly looking at types of blood cancer due to its accessibility in comparison to cancer of other areas of the body. In 2010 Rosenberg described chimeric antigen receptor (CAR) therapy, in which a patients T cells are genetically engineered to express a receptor that allows them to target specific cells, in this case cancerous cells. This is also referred to as T cell “re-education”.
Now a team of researchers at the Memorial Sloan-Kettering Cancer Centre in New York has published new data from a study using their CAR, 19-28z. This specific CAR targets the marker CD19, also known as B-lymphocyte antigen, which is present on another type of immune cell, the B cell. These cells are normally involved in antibody production and in providing one type of the long-lasting immunological memory, but as with many cell types when things go wrong they can become malignant, cancerous. Adult B cell acute lymphoblastic leukemia (ALL) is a form of blood cancer caused by malignant B cells that have yet to fully mature. Importantly therapies targeting B cells expressing CD19 would not affect fully matured B cells, or plasma cells which do not express CD19. As mentioned previously these cells are responsible for the vital mechanisms of antibody production and immunological memory, hence these hugely important aspects of the immune system would survive treatment with CD19-targeting therapies, whereas (hopefully) the cancerous CD19 positive cells would not. Interestingly, other studies have shown that CD19 may in fact be directly involved in the development of some cancers making the choice of targeting this molecule even more attractive.
In their latest study the researchers showed that, in a group of 16 patients, 88% showed a complete response to the CAR therapy. This means that 14 of the 16 were able to reach complete remission and then begin hematopoietic stem cell transplant to maintain this state. These patients had previously relapsed from remission after standard treatments and so had been offered this treatment instead of salvage chemotherapy, which is only effective in 30% of relapsed ALL patients. These results build on the 2013 data by the same group that first showed that 19-28z CAR was well-tolerated and showed significant ability to treat relapsed ALL. Unfortunately there are some adverse risks with this treatment. Some patients have shown markedly increased levels of serum cytokines in what is known as severe cytokine release syndrome (sCRS). This is treatable with corticosteroids amid other therapies but it is essential that research is undertaken to identify those patients who are likely to develop this issue. CAR therapy is at its heart a personalised medicine and so understanding these adverse effects and their likelihood between different people is of great importance. Adverse effects aside, the researchers and the data, which speaks for itself (88% v 30% seems like an obvious choice to me), claim that this treatment is deserving of moving on to phase II trials. Steven Rosenberg said in a paper in 2013 that anti-CD19 CAR T cells could become the standard therapy for some B cell cancers and it seems that this latest data supports this. It has been a long road for cancer immunotherapy but with results like this from an ever more popular field of research, one can hope that soon there will be multiple therapies of this type advancing to the point where they become the standard-of-care and herald a new era of personalised cancer treatment.