Targeting novel immune-suppressive pathway encourages further testing
Early studies show that the treatment is safe, shrinks some tumours, and candidate marker may predict response
- Date : 13 Jun 2012
- Topic : Personalised medicine
Two clinical trials led by Johns Hopkins Kimmel Cancer Centre researchers in collaboration with other medical centres, testing experimental immune drugs, have shown promising early results in patients with advanced non-small cell lung cancer (NSCLC), melanoma, and renal carcinoma. More than 500 patients were treated in the studies of two drugs that target the same immune-suppressive pathway, and according to the investigators there is enough evidence to support wider testing in larger groups of patients.
Results of the phase I clinical trials are published online June 2 in The New England Journal of Medicineand presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (1-5 June, Chiaco, USA).
Based on the positive response rates to these drugs and duration of many of these responses, new clinical trials will move forward. The results from preliminary analysis presented by Dr Suzanne Topalian, professor of surgery and oncology at Johns Hopkins, show that among responding patients who were followed for more than one year responses were maintained for more than one year in two-thirds of those treated in one trial and in half of those in the other trial.
The immune-based therapies tested in the two clinical trials, both made by Bristol-Myers Squibb, aim not to kill cancer cells directly, but to block a pathway which includes two proteins called programmed death-1 (PD-1), expressed on the surface of immune cells, and programmed death ligand-1 (PD-L1), expressed on cancer cells. When PD-1 and PD-L1 join together, they form a biochemical structure protecting tumour cells from being destroyed by the immune system. Another protein involved in the pathway and also expressed by cells in the immune system, programmed death ligand-2 (PD-L2), was originally discovered by Johns Hopkins investigators.
To make cancer cells more vulnerable to attack by the immune system, investigators tested each of two drugs, BMS-936558, which blocks PD-1, and BMS-936559, which blocks PD-L1, in separate clinical trials conducted at multiple USA hospitals. The drugs are given intravenously in an outpatient clinic every two weeks, and patients can remain on the treatment for up to two years.
The PD-1 blocking drug was tested in 296 patients with various advanced cancers who had not responded to standard therapies. Of those patients receiving the anti-PD-1 therapy, 240 who started treatment by July 2011 were analysed for tumour response. Significant tumour shrinkage was seen in 14 of 76 (18%) non-small cell lung cancer patients, 26 of 94 (28%) melanoma patients and nine of 33 (27%) renal carcinoma patients.
In this trial, some patients experienced stable disease for six months or more, including five of 76 (7 %) lung cancer patients, six of 94 (6 %) melanoma patients and nine of 33 (27%) renal carcinoma patients. The response in multiple tumours and especially NSCLC, which is typically not responsive to immune-based therapies, make this a promising avenue of research. It was surprising that no responses were seen in prostate cancer or in colorectal cancer patients.
The anti-PD-L1 therapy also showed responses among 207 treated patients. Five of 49 (10%) NSCLC patients, nine of 52 (17%) melanoma patients, and two of 17 (12%) renal carcinoma patients responded.
The results from both drugs give a good indication that the PD-L1/PD-1 pathway is an important target for cancer therapy. Additional clinical studies will be needed to determine the drug's potential impact on survival.
The anti-PD1 therapy caused serious toxicities in 41 of 296 (14%) patients. Many of the toxicities were immune-related, including colon inflammation, thyroid abnormalities and three deaths from pneumonitis. The study investigators are working with colleagues across the USA to develop better methods for early detection and effective treatment of pneumonitis. Other less severe toxicities included fatigue, itching and rash. The anti-PD-L1 therapy caused 9 % serious toxicities and no deaths.
Early results indicate that PD-L1 expression in pretreatment tumour biopsies may correlate with clinical response to anti-PD-1 therapy
Among patients receiving anti-PD-1, tumour samples collected from 42 study patients before they received the experimental therapy were evaluated at Johns Hopkins Medicine for molecular markers that may correlate with clinical response. The investigators found PD-L1, the partner protein to PD-1, in 25 of the 42 samples. Nine of the 25 patients with PD-L1-positive tumours experienced tumour shrinkage as compared with none of the patients with PD-L1 negative tumours. The use of PD-L1 as a biomarker will be explored further.
The two therapies targeting the PD-1/PD-L1 pathway are in the same class of antibody therapies, and the researchers have just scratched the surface of laboratory and clinical research on these drugs. This early success will lead to controlled clinical registration trials soon, specifically in patients with NSCLC, melanoma, and renal cell carcinoma. Ultimately, the researchers envision boosting the effectiveness of the therapy by combining it with other anti-cancer agents, including cancer vaccines.
Funding for the clinical studies was provided by Bristol-Myers Squibb and Ono Pharmaceuticals Co., Ltd. Research support was provided by grants (CA142779 and CA006973) from the USA National Cancer Institute at the National Institutes of Health and the Melanoma Research Alliance.
Four study researchers have served as consultants to Bristol-Myers Squibb, and Dr Topalian is the Chief Scientific Officer of the Melanoma Research Alliance. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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