The CAR T phenomenon

Let’s face it, we are all going to get cancer one day. We are living much longer, people are not giving up smoking, there is the occasional nuclear power plant leak, the ozone layer is still disappearing, and a host of other factors ensure that we are probably being exposed to an ever-increasing variety of carcinogenic substances. It’s no wonder drug companies are pouring so much money into cancer therapy development. There is a huge market and it also helps that cancer drugs are easier to get past regulatory authorities. Cancer patients are not particularly nit-picky about the side-effects of a drug if there exists hope that it can get rid of that inevitable death sentence.

Cancer therapy has undergone much progress in recent years. Where in the past, doctors had only surgery, chemotherapy and radiation to rely on, now there is a wide range of cancer-subtype specific therapies to choose from, mostly in the form of biologics. These include monoclonal antibodies, cancer vaccines, cytokine treatment, cancer-killing viruses, gene-therapy and even bacteria!

Currently, there has been a growing interest among pharmas on chimeric antigen receptor T cell immunotherapy or CAR T for short. Merck recently signed a US$941 million deal with Intrexon for their CAR T technology. Pfizer paid $110 million (with a potential to go up to $2.8 billion) for Celletics CAR T tech, and Novartis is also heavily invested, working with scientists from Penn Medical school that were the first to develop the technology. Various other biotechs specializing in this technology – Juno Therapeutics, Kite Pharma and Bluebird Bio – have also managed to raise incredible amounts of money within a short time-frame. The CAR T phenomenon as I call it, where everyone cannot stop throwing money into it.

CAR T therapy basically involves growing T cells from the affected patient (personalized therapy ftw) in culture, getting them to express CARs which target the cancer cells (usually CD19 is targeted that is primarily expressed on malignant B cells) alongside several moieties that increase the activity of T cells, and infusing them back into the patient where they target and kill cancer cells. Why is it being touted as the next big thing in cancer therapy? Primarily because of the impressive clinical trial results. One of the first in-human trials performed at the US National Cancer Institute in 2010 saw 6 out of 7 patients gaining partial or complete remission, with significant and sustained depletion of B cells and regression of adenopathy. Subsequent trials by Memorial Sloan-Kettering Cancer Center and University of Pennsylvania have all reported remission of malignancies lasting up to several months. This guy has been cancer-free for four years. In a larger trial sponsored by Novartis at the Children’s Hospital of Philadelphia, 27 out of 30 patients treated showed complete remission, with 19 remaining in remission as of Oct 2014. Several more trials are on-going to date, but the striking positive data seen so far have left many thinking that this may be the future of cancer therapy.

As usual, there are obstacles to overcome. Patients typically show rather acute adverse effects such as fever, fatigue, and hypotension that is usually accompanied by an increase in cytokine levels. The recent Philadelphia trial utilized another treatment tocilizumab, an anti-IL-6 receptor mAb to reduce this spike in cytokine levels. As such, there is a growing trend of combination therapies in an effort to increase the efficacy or reduce toxicity of treatment. There is a heightened interest in particular with immune checkpoint inhibitors – targeting PD-1 and CTLA-4 for example – that are said to increase T cell activity towards killing cancer cells. CAR T therapy also works primarily with non-solid tumours though several groups are now exploring their usage in solid tumour cancers.

Interestingly, genetics may also play a significant role in cancer immunotherapy. Patients with malignant melanoma treated with immune checkpoint CTLA-4 inhibitor3 for example, showed responses that varied with mutational signatures determined by exome sequencing. A researcher was quoted saying “The more mutated the tumor’s genome is, the more likely it is that immunotherapy will work.” A possible basis for the dramatic change in fate of pretty far along cancer patients that underwent CAR T therapy? With the excessive amount of funding going into CAR T, I hope we fully understand the specifics on how it works in future!

Sources:

1. James N. Kochenderfer & Steven A. Rosenberg. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nature Reviews Clinical Oncology 10, 267-276 (May 2013) doi:10.1038/nrclinonc.2013.46

2. CAR T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancers – by National Cancer Institute

3. Alexandra Snyder, Vladimir Makarov, Taha Merghoub, Jianda Yuan, Jesse M. Zaretsky, Alexis Desrichard, Logan A. Walsh, Michael A. Postow, Phillip Wong, Teresa S. Ho, Travis J. Hollmann, Cameron Bruggeman, Kasthuri Kannan, Yanyun Li, Ceyhan Elipenahli, Cailian Liu, Christopher T. Harbison, Lisu Wang, Antoni Ribas, Jedd D. Wolchok, Timothy A. Chan. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. New England Journal of Medicine, 2014; 141121104951001 DOI: 10.1056/NEJMoa1406498

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One thought on “The CAR T phenomenon

  1. Pingback: CRISPR trial in humans – a look at checkpoint inhibitors | Bioshots

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