PD-1 inhibitors in cancer therapy

PD-1 is a receptor which, through a variety of metabolic processes, leads to inactivation of T cells. In the therapy of the cancer, one of the promising new drugs is BMS-936 558, an antibody directed against PD-1 receptor. The effectiveness of the new therapy has been demonstrated in large randomized trials for renal cancer, non-small cell lung cancer and melanoma. Currently, the drug is in the second phase of clinical trials (treatment of renal cell carcinoma). The obtained results are very promising, however the effect of the antibody must be evaluated in the further studies.

PD-1 (Programmed cell death 1 receptor) are receptors, that inhibit the activation of the T cells. It has a central role in immune processes, but can also repress the anti-tumor and anti-viral T cell response. The way of PD-1 interaction, in the metabolic processes, has not been yet completely understood. Blockade of PD-1, expressed by T cells, can help to improve the efficiency of the body’s immune system.

An antibody, which blocks PD-1 receptor in a specific way, is BMS-936 558.
Some studies were carried out [1] in order to assess the effect of anti-PD-1, as a potential therapy of cancer. For the experimental treatment were qualified patients with a renal cancer, lung cancer (non-small cell carcinoma), prostate cancer resistant to surgery, with advanced form of melanoma and colorectal cancer. The study was conducted on a group of 296 patients. The antibody anti-PD-1 was administered every 2 weeks, at a dose between 0.1 and 10.0 mg per kilogram of body weight. Patients were evaluated after each 8-week cycle. Endpoint of the therapy was a disease progression or a complete response to the treatment. By that time some patients received up to 12 cycles of therapy.

The results of the drug action could be evaluated in 236 patients. Response (complete or partial) was observed in patients suffering from non-small cell lung cancer, melanoma and renal cell carcinoma. There was a cumulative response rate of 18% in patients with non-small cell lung cancer (14 of 76 patients), 28% of patients with melanoma (26 of 94 people involved in the study) and 27% in patients with renal cell carcinoma (9 of the 33 patients). In most cases, clinical response lasted for over a year. 14% of patients reported side effects of grade 3 and 4, in 3 cases, the death from toxic pulmonary effects took place.

In order to better understand the role of PD-1 in the regulation of metabolic pathways, immunohistochemical analysis were performed on histological samples, obtained from 42 patients. None of the patients without PD-1 receptor responded to the treatment. In 36% of patients expressing the receptor PD-1, a positive response to therapy was observed.

Preliminary results suggest a correlation between the expression of PD-1 receptor and response to treatment. A positive response to the administration of the antibody was observed in case of one in four / five patients. Improvement was observed only in the case of non-small cell lung cancer, melanoma and renal cell carcinoma. Side effects do not preclude the future use of BMS-936558 on a larger scale. The results of the presented above therapy are promising, but further research on the drug should be done.

Nowadays there also trials to use BMS-936558 for advanced / metastatic renal cell carcinoma (RCC) [5]. At present, the drug is in the second phase of clinical trials. Improvement is assessed by radiographic images of the tumor and by collecting data on deaths of people involved in the program. During the first year of therapy, the tumor is assessed every 6 weeks, then every 3 months.

The study involved those, with histological diagnosis of renal cell carcinoma, previously treated with anti-angiogenesis drug, that had no more than 3 cycles of chemotherapy to local tumor or metastases. People taking part in the study could not have any autoimmune disease (present or past).

The results are not yet known, preliminary ones will be available in November 2012.


Currently, the anti-PD-1 antibodies appears to be one of the most promising therapies in oncology. This drug is mainly used in case of renal cell carcinoma, which replies well to the immune therapy. BMS-936 558 is in the second phase of clinical trials, its effects must be evaluated in the further studies.



Written by: Magdalena Mroczek


Source:
1.N Engl J Med. 2012 Jun 28;366(26):2443-54. Epub 2012 Jun 2. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.Topalian SL i współ. 2011 Sep 1;9(9):1011-8.
2.Role of immunotherapy for renal cell cancer in 2011.
George S, Pili R, Carducci MA, Kim JJ. Cell Cycle. 2012 Oct 3;11(23). [Epub ahead of print]
3.PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A.
Patsoukis N, Sari D, Boussiotis VA.
4.http://www.futuremedicine.com/doi/book/10.2217/9781780840024
5.http://clinicaltrials.gov/show/NCT01354431



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