by Justina Hurley
Research into immunotherapy seems to be bringing positive results as the trial of a new drug known as anti-PDL1 (MPDL3280A) is showing.
Cancer is ultimately an immune system failure but this can be triggered by various factors. In cases where a patient has tested positive for PD-L1, this means that the cancers cells essentially use PD-L1 to fool the immune system and so essentially sneak past the immune system soldiers namely the T-cells. MPDL3280A switches off PD-L1 and this can help to activate the T cells so that they can one again, restoring detect and attack tumour cells.
The trial included patients with melanoma or cancers of the lung, kidney, colon, GI tract, or head and neck, whose tumors were evaluated for PD-L1 and also included a sub group of patients with terminal bladder cancer.
The trial differed from other immune therapy trials in that it incorporated serial biopsies of patients before and during treatment to identify a tumor profile that predicts response to treatment, said the paper’s first author, Roy Herbst, Ensign Professor of Medicine at Yale Cancer Center, professor of pharmacology, and chief of medical oncology in Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven.
“We knew that the expression of PD-L1 in tumor cells is critical in blocking the immune system so we were intrigued to find that the expression of PD-L1 in non-tumor cells such as macrophages also predicted drug response,” said Herbst.
The serial biopsies revealed the characteristics of both functional and non-functional immune responses and provided a baseline for how patients respond and don’t respond to treatment.
“We can begin learning how to use combination therapies to affect the immune response cycle,” Herbst said.
Of the 175 patients enrolled, 21% showed partial or complete response to MPDL3280A, with some being rapid and durable. Across all tumor types, 46% of patients with high PD-L1 expression on non-tumor cells showed a partial or complete response. Also notable was the finding that smokers responded better to the drug than non-smokers. This could provide insight into how smokers and nonsmokers respond differently to drugs, said the researchers.
Herbst said the drug is in phase II and III trials at Yale.
Also published in the same issue of Nature are additional findings from this same trial, including the response of advanced bladder cancer patients who did not respond to other treatments. This expansion arm study was co-authored by Thomas Powles of Queen Mary University Hospital of London with Daniel P. Petrylak, professor of medicine and urology at Yale Cancer Center, and Joseph Paul Eder, professor of medicine at Yale Cancer Center. Petrylak presented the findings earlier this year at ASCO’s annual conference.
“It is encouraging that a trial that began in lung, melanoma, and renal cancer expanded to bladder cancer, another smoking-related cancer, with such promising results,” Herbst added.
The bladder cancer patients also had a very positive response. After 12 weeks, there was a positive response in up to 52% of the people treated and 2 people had a full recovery i.e. the cancer was gone.
What is interesting is that people who were PDl1 negative were also treated and also showed a very good response to the drug.
All in all a great step forward in cancer research and it also emphasise the role of the immune system as ultimately it is our own immune system that is stepping in to get rid of the cancer, the role of the drug is to show the immune system where the cancer is hiding so that it can mobilise and send in its attack troops!
The findings were published in the Nov. 27 edition of the journal Nature.
About the study:
- The study included 30 patients who were identified as PD-L1 positive (immunohistochemistry [IHC] 2/3) using an investigational PD-L1 diagnostic test being developed by Roche.
- After six weeks of follow-up, the objective response rate (ORR) as measured by RECIST criteria was 43 percent (13/30), and after 12 weeks, ORR was 52 percent (13/25) in people with PD-L1-positive tumours.
- A complete response (no radiographic evidence of tumour) was observed in 7 percent of PD-L1-positive patients (2/30).
- The ORR was 11 percent (4/35) in people whose tumours were identified as PD-L1-negative (IHC 0/1) by our investigational test.
- People in the study experienced a median time to response of 42 days.
- Treatment-related Grade 3 AEs occurred in 4 percent (3/68) of people in the study and included weakness (asthenia; 2 percent), low platelet count (thrombocytopenia; 2 percent) and low phosphate levels (blood phosphorus decrease; 2 percent).
- The most common AEs observed to date occurring in more than 5 percent of patients were decreased appetite (12 percent), fatigue (12 percent), nausea (12 percent), fever (pyrexia; 9 percent) and weakness (asthenia; 7 percent).
What is MPDL3280A?
MPDL3280A (also known as anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. MPDL3280A is designed to target PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells.