Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Targeted antibody, immune checkpoint blocker rein in follicular lymphoma

12.12.2013
Combination therapy sparks complete responses in 52 percent of patients in clinical trial

One drug attacks tumor cells directly, the other treats the immune system by taking the brakes off T cell response. Together, they put half of the patients with relapsed follicular lymphoma into complete remission in a phase II clinical trial at The University of Texas MD Anderson Cancer Center.

"Most drugs target only the tumor, this combination is complementary, treating both the lymphoma cells directly and the T cells in a manner that activates them against cancer cells," said senior author Sattva Neelapu, M.D., Ph.D., associate professor of Lymphoma/Myeloma at MD Anderson and senior author of the paper out in The Lancet Oncology.

"The combination of the established antibody drug rituximab with the experimental drug pidilizumab so far also has a remarkably mild side effect profile," Neelapu said.

Of 29 study participants at a median follow-up of 15.4 months, 19 (66 percent) had either a complete or partial response, with 15 (52 percent) having a complete response.

There were no grade 3 or 4 adverse events, with all effects at the less serious grade 1 and 2 levels. Patients had no indicators of autoimmunity, which can be an issue in the class of drugs that blocks immune system checkpoints and activate T cells. Such mild effects are particularly important for follicular lymphoma patients, who are diagnosed with the disease at a median age of 60.

"Rituximab treatment alone usually achieves a 40 percent overall response rate and about 11 percent complete responses," Neelapu said. "And the side effect profile of the combination is about the same as rituximab alone. Adding pidilizumab greatly improves responses so far at little cost in additional side effects."

Drug targets PD-1 receptor to unleash immune response

The immune system usually recognizes and destroys abnormal cells, in addition to viral and bacterial infections, but cancer relies on immune checkpoints to evade attack. One of these is the programmed cell death 1 (PD-1) receptor, which stymies T cell function when activated by ligands highly expressed in tumor cells. Pidilizumab blocks PD-1, and like other drugs that impair immune checkpoints, should unleash T cells to attack cancer cells.

Immune checkpoint blockade was pioneered by James Allison, Ph.D., now chair of MD Anderson's Department of Immunology. He worked out the basic science of checkpoints and developed the first drug to block one. Ipilimumab (known commercially as Yervoy) blocks CTLA-4, another checkpoint.

Neelapu grew interested in checkpoint blockade after years of research developing vaccines to treat cancer. "Vaccines induce an immune response to cancer, but we don't see objective response in the tumors," Neelapu said.

Research showed PD1 is highly expressed on T cells in the bloodstream and tumors of follicular lymphoma patients and also is associated with impaired T cell function. Pidilizumab is a monoclonal antibody that targets PD1. A phase 1 trial had shown it to be safe, so Neelapu and colleagues combined it with rituximab (known commercially as Rituxan), another monoclonal antibody that hits CD20, a surface protein on immune system B cells. Follicular lymphoma is a cancer of B cells.

No dose reductions or treatment halt required

Patients had gone through 1-4 previous treatments before enrolling in the clinical trial between January 2010 and January 2012. Of 32 patients enrolled, two were ineligible to proceed and were not treated and one withdrew from the trial after one infusion of pidilizumab and received alternate treatment.

None of the 29 remaining patients received a dose reduction or discontinued treatment due to adverse events. Median progression-free survival for all patients was 18.8 months but had not been reached for the 19 responders. Median response duration for responders was 20.2 months, with only seven having disease progression as of May 2013.

The research team examined blood samples and tumor biopsies to identify possible risk factors and genes that might indicate response to treatment and survival.

Gene expression predicts progression-free survival

"Gene expression analysis of tumor samples from 18 patients before treatment showed that progression-free survival increased for patients when their gene signature included genes that are highly active during T cell response or repressed in regulatory T cells that dampen T cell activation," said Eric Davis, M.D., associate professor of Lymphoma/Myeloma and co-senior author of the paper.

The team also identified 41 genes that are more highly expressed in effector T cells with anti-tumor effects compared with follicular helper T cells, thought to have pro-tumor effects. Low expression of the 41-gene signature predicted less tumor shrinkage and shorter progression-free survival at 12.7 months. Median progression-free survival was not reached for patients with high signature expression.

"These findings indicate that patients who already have an active immune response before treatment do better on this combination," said co-first author Jason Westin, M.D., assistant professor of Lymphoma/Myeloma.

Core-needle biopsies from eight study participants after treatment showed increased expression of T cell activation genes, which was associated with longer progression-free survival.

When the researchers analyzed the 41-gene signature in 191 cases of follicular lymphoma patients treated with chemotherapy alone, it did not predict a significant difference in overall survival. It's likely, the researchers noted, that the signature only has predictive power for the combination treatment.

Randomized trial, new combinations

Since patients received only the combination therapy, the next step would be a randomized, double-blind trial comparing it to rituximab alone.

A commentary by two French oncologists also published in The Lancet Oncology noted: "The demonstration of activity in relapsing diffuse large B cell lymphomas suggests that anti-PD1 antibody therapy might have a therapeutic role in all lymphomas."

"Our findings indicate rituximab and pidilizumab together are safe and highly active in follicular lymphoma," Neelapu said. New combinations might add other checkpoint blockade drugs, such as ipilimumab, the B cell receptor inhibitor ibrutinib or lenalidomide, which also activate immune system.

Chemotherapy could be added as well, Westin said, but that would likely increase side effects.

Co-authors with Neelapu, Davis and Westin are co-lead author Fuliang Chu, Ph.D., Min Zhang, Ph.D., Luis Fayad, M.D., Larry Kwak, M.D., Nathan Fowler, M.D., Jorge Romaguera, M.D., Fredrick Hagemeister, M.D., Michelle Fanale, M.D., Felipe Samaniego, M.D., Zhiqiang Wang, Ph.D., Wencai Ma, Ph.D., and Yanli Gao, all of Lymphoma/Myeloma; Lei Feng and Veerabhadran Baladandayuthapani, Ph.D., of Biostatistics; Michael Wallace, M.D., of Interventional Radiology; Luis Vence, Ph.D., and Laszlo Radvanyi, Ph.D., of Immunology; Tariq Muzzafar, M.D., of Hematopathology: and Rinate Rotem-Yehudar, Ph.D., of Cure Tech, Yavne, Israel.

Chu, Zhang, Kwak, Wang, Ma, Vence, Radvanyi, Davis and Neelapu also are affiliated with MD Anderson's Center for Cancer Immunology Research.

This research was funded by grants from the National Cancer Institute of the National Institutes of Health (R21 CA143785, R01 CA155143) and MD Anderson's Cancer Center Support Grant from the NCI (CA16672) and an NIH Clinical and Translational Science Award (Ul1 RRO24148), the Leukemia and Lymphoma Society, and Cure Tech, which supplied pidilizumab.

Scott Merville | EurekAlert!
Further information:
http://www.mdanderson.org

More articles from Studies and Analyses:

nachricht Real-time feedback helps save energy and water
08.02.2017 | Otto-Friedrich-Universität Bamberg

nachricht The Great Unknown: Risk-Taking Behavior in Adolescents
19.01.2017 | Max-Planck-Institut für Bildungsforschung

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>