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 Smart Data Transformation – Surfing the Big Wave
02.12.2016 | Fraunhofer-Institut für Angewandte Informationstechnik FIT

nachricht Climate change could outpace EPA Lake Champlain protections
18.11.2016 | University of Vermont

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: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>