Cancer: CARs in the Fast Lane

12. April 2016
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Until recently, cancer therapy using genetically modified T-cells was an obscure treatment option and one which was only known to a few specialists. Now though more and more studies are reporting unusual successes – but also significant side effects.

At the annual meeting of the American Association for the Advancement of Science (AAAS), gene therapy using CAR-T-cells (chimeric antigen receptor) were a big topic. Dr. Stanley Riddell from the Fred Hutchinson Cancer Research Center in Seattle presented a summary of recent study data there and reported response rates above 80% among patients with difficult to treat haematologic malignancies.

“To be honest, it is unprecedented in medicine to obtain response rates at this level with these very advanced patients”, says Riddell [Paywall]. Another participant, Dr. Chiara Bonini of the San Raffaele University in Milan, stressed that these results really leave others which came before them in the dust: “This really is a revolution”. No wonder then that many in the media have reported about the alleged breakthrough in cancer therapy.

Modified T-cells working as cancer-sniffing dogs

In this new form of immunotherapy, T-cells of patients’ blood are genetically engineered in such a way as to carry a chimeric antigen receptor, wherein the antigen-binding site of a monoclonal antibody domain is connected to an intracellular signaling domain via a transmembrane domain. In contrast to physiological T-cell receptors, CARs can recognise unprocessed antigens and are not dependent on the antigens being presented as part of an antigen-MHC complex. The receptor transgene were funneled into the T-cells of the patient by means of viral vectors. Following the multiplication of the CAR-expressing T-cells, they are transfused back into the patient; there they can track down the antigen-carrying cancer cells.

The best studied CAR-T-cell therapy until now has been that done on relapsed or refractory B-cell malignancies: in cases involving patients with chronic lymphocytic leukemia (CLL) remission rates of approximately 45% were able to be achieved using methods targeted at CD19 CAR-T-cells, and the modified T-cells survived for over 4 years in some patients. In cases of acute lymphoblastic leukemia (ALL) remission rates of 70% – 90% were able to be achieved, nonetheless cell survival appears to be shorter than in CLL – in most of the studies, the modified T-cells were detectable for only a few months.

Aside from CD19 there are also other molecular targets that are being studied in clinical trials. These include other members of the CD family of molecules, as well as others such as HER2, GD2, EGFR, PSMA, interleukins, ErbB and ROR1. The indications are non-Hodgkin’s lymphomas such as B-cell lymphoma [Paywall] and mantle cell lymphoma, sarcoma [Paywall], neuroblastoma and glioblastoma [Paywall]. Furthermore CAR T-cell therapies used on prostate, breast cancer and ovarian cancer are currently being studied in phase I clinical trials.

Deadly therapeutics

The American oncology specialists’ society ASCO has in its most recent annual report labelled CAR-T-cell therapy a unique new strategy. The results so far are promising, according to the authors, but they say it is unclear whether CAR-T-cell therapy will have broader applications, since studies heretofore have been small and limited to patients with difficult to treat malignancies. In addition, the authors refer to the considerable toxicity of the treatment.

In fact, a course of CAR-T-cell therapy can be associated with significant side effects which permit classfication in three groups [Paywall]: on-target on-tumour, on-target off-tumour and off-target off-tumour. The on-target on-tumour side effects include cytokine-release syndrome (CRS) and tumor lysis syndrome (TLS). Both are potentially life-threatening syndromes. A CRS event is created when large amounts of inflammatory cytokines are emitted by the massive-scale activation of the immune system. Acute fever, cardiac dysfunction, acute respiratory distress, neurological toxicity, kidney or liver failure, and disseminated intravascular coagulation (DIC) may result. Encephalopathy and seizures, the cause of which is unclear, can also occur, independently of CRS

B-cell aplasia as a good biomarker

On-target off-tumour toxicity arises from the fact that the antigen used for the preparation of the CAR T-cells is not only expressed on the cancer cells, but also in non-malignant tissues of the body. One such example is B-cell aplasia, which occurs in association with CD19 CARs, because CD19 is a B-cell surface protein which is expressed throughout B-cell development – therefore not just present on cancer cells but is also present on B-cells. Fortunately, a B-cell aplasia is amenable to being treated via immunoglobulin replacement therapy – in actual fact enduring B-cell aplasia even seems to be a good biomarker for the activity of CAR T-cells. In contrast, a T-cell aplasia would be fatal so that T-cell malignancies cannot be immediately treated using CAR-T-cell therapy.

Chronic off-target off-tumour toxicity events have only been observed in animal models. There seems to be distortion of normal homeostatic cell responses that develop into toxicities over time due to permanent CAR-T- cell activity. With mice specifically, weight loss and cachexia occurred leading to death two months after CAR- T-cell infusion. Dissection revealed that the animals suffered from granuloma-type tissue neoplasms in the spleen, liver and lymph nodes.

The future of CAR-T-cell therapy

Not only does the specific design of the modified antigen receptor have an influence on the success and the toxicity of the CAR-T-cell therapy — it also has an influence on the pretreatment of the patient. Without pretreatment in the form of chemotherapy, treatment using CAR-T-cells has little therapeutic effect because regulatory T-cells (Tregs) and myeloid suppressor cells inhibit the CAR T-cell-mediated immune response [Paywall] . Equally, the volume of CAR-T-cells supplied plays a role: an infusion with a low dose of CAR-T-cells would indeed be able to reduce toxicity, but at the same time could lead to a loss of antigen expression on the tumour cells through the selective pressure of therapy, through which an immune evasion may develop. High doses of CAR-T-cells can by contrast intensify cytokine release syndrome and tumour lysis syndrome and thus lead to higher toxicity.

In addition, the trend seems to be towards not seeing CAR-T-cells as the sole miracle weapon for use against cancer, but rather to combine this approach with other immunotherapies. “Just like most cancer therapies, CAR-T- cell therapy is best seen as part of a multimodal treatment concept”, Dr. Catherine Bollard [Paywall] from the Children’s National Medical Center in Washington also believes. “The ultimate strategy would be to combine CAR T-cells with other targeted cancer therapeutics, such as small molecule inhibitors, antibodies, checkpoint inhibitors, and so on”.

At the same time she also warns against becoming too set on needing CAR-T-cell therapy. “There are currently other T-cell-mediated therapies being developed, for example BITE antibodies and multi-antigen-specific T- cells. Some of these therapies have also shown very promising clinical results on patients with a poor prognosis. Therefore we should be open to all developments”.

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dr bert oelbrandt
dr bert oelbrandt

a schematic drawing would be useful here

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