T cells for patient-specific cancer treatment

T cell therapy is an investigational approach that is being assessed for the patient‑specific treatment of cancer. T cells can recognise and kill cancer cells; by making large numbers of such cells, we can potentially treat large and metastatic cancers.

In adoptive T cell therapy, relatively large numbers of cancer specific T cells are generated outside the body and then re‑infused. Cancer‑specific T cells can be made in three ways:
* From blood: rare cancer‑specific T cells can be identified and isolated from the blood and then grown in large numbers.
* From tumours: some tumours contain relatively large numbers of T cells, which can be isolated.
* By genetic modification: normal T cells can be genetically modified to endow them with cancer specificity. There are a variety of ways to do this. The simplest is to use natural “T cell receptors” isolated from cancer‑specific T cells. Another way would be to use an artificial T cell receptor (a variety of artificial T cell receptors are available). These may be more effective than natural receptors because they enable better recognition of cancer cells and also enhance the activity of the engineered T cells.

How is treatment administered?
The simplest way to administer T cell treatment would be to grow them from blood samples in the laboratory and then re‑infuse larger numbers. However, T cells do not generally survive well if they are given in this way.

Based on preclinical and clinical research, we now know that the chance of survival of the infused cells is greater in patients that have been pre‑treated with lympho‑depleting, but non‑myeloablative chemotherapy. In fact, there is also a chance that the cells multiply post-infusion if administered in pre‑treated patients. This multiplication is the result of a phenomenon known as “homeostatic expansion” — the chemotherapy depletes normal T cells and the body then produces cytokines, such as IL7 and IL15, which support the survival and proliferation of the infused cancer‑specific T cells.

Interleukin‑2 (IL2) is often administered in conjunction with T cell therapy; however, the precise value of IL2, or indeed of any other cytokines in this scenario, is the subject of ongoing research.

The current situation
A large amount of preclinical research and some early‑stage clinical research has been conducted with T cell therapy. So far, preclinical studies have shown good efficacy. In the clinic, the most successful therapy has been that which uses specific T cells selected from patients’ tumours. This approach has been successfully used to treat advanced melanoma in relatively large numbers of patients both in the US and in Israel; the results can be quite spectacular in around 50% of patients treated. Efforts are ongoing to both reduce toxicity and improve the applicability. We plan trials of this approach to start late in 2010 in Manchester (UK); this is the highest priority for our new Cellular Therapeutics unit.

Trials of genetically engineered T cells are at an earlier stage of development. Again, trials in melanoma have shown some successes at the National Cancer Institute in Washington (USA). Trials in Manchester focus on using T cells targeted to gastrointestinal cancer or lymphoma, using artificial receptors, which produce excellent preclinical activity. The trials are ongoing and are some of the first in the world to combine chemotherapy and IL2 with engineered T cells using artificial receptors. The trial targeting gastrointestinal cancers will finish towards the end of 2010, but the results look encouraging so far.

Will cost hinder uptake?
This type of therapy could be applicable to a whole range of cancers. However, it is a patient specific treatment that requires production of a large number of cells to a GMP standard in a short period of time for an individual patient — this poses a number of challenges:* Production must be flexible and allow the production of multiple different products for multiple patients simultaneously. Our new Cellular Therapeutics Unit has been designed around custom built isolators with this in mind and should be able to process cells for up to 10 patients at the same time.
* The process currently requires considerable skill and some individualisation. Ideally, it would become more automated in the future to reduce cost and improve reproducibility.
* The cost of the treatment is relatively high because of the individualised nature of the treatment. There are two components to the cost:
1. The cost of cell production. This can be streamlined and reduced to some extent, but the patient‑specific nature means it will always be relatively high.
2. The clinical costs are high because of the associated use of chemotherapy and IL2, which require inpatient treatment. Improvements to the methods are likely in the next few years and these will reduce the cost.

Even though the cost is high, the benefits are large (currently for melanoma patients at least) and the key advantage is that this is a one‑off treatment that has long‑lasting benefits. Thus, even at this early stage of development, the cost benefit is probably comparable to other new cancer treatments, which typically require continued use for months or years.

Based on a contribution by Professor Robert Hawkins, Cancer Research UK Director of Medical Oncology at Christie Hospital, Manchester (UK).