Personalized immunotherapy research leads to more complex clinical trials

It looks at ways to boost patient's immune system

A new approach to personalized medicine is resulting in phase I and phase II clinical trials that rely on extensive, hands-on investigator and clinical research (CR) staff training, and these types of studies are creating both new challenges and opportunities for North American CR sites.

Personalized medicine, including gene therapy, is the wave of the future, says Anthony T. Dren, PhD, a consulting professor with the Duke University School of Medicine in Durham, NC. "This is an evolving trend that I think is a very worthwhile approach," Dren says.

The advantage to the personalized immunotherapy or medicine approach is that it should minimize immune reactions since the person is being given a product derived from their own body's cells, Dren notes.

Three clinical trials involving personalized immunotherapy are underway for the testing of new treatments for HIV and cancer. Sponsored by Argos Therapeutics of Durham, NC, the trials involve a much more complex process than the typical therapeutic trial, says Rafick-Pierre Sékaly, PhD, a professor in the department of microbiology and immunology, and a Canadian research chair in human immunology at the Université de Montréal in Quebec, Canada. Sékaly is studying the personalized immunotherapy approach in HIV patients.

"It's not like you are just injecting a drug that you're testing," Sékaly says.

This personalized medicine approach follows a trend of the past decade, as investigators and physicians try to find improved and less toxic ways of treating patients through treatment that is geared to the particular landscapes of a patient's own body.

"Personalized medicine is here, and it's just going to become more prevalent," says Jeffrey Abbey, MBA, JD, vice president of business development for Argos Therapeutics.

"There are a number of different ways to go about personalized medicine, and a lot of research is looking at it from a genetics perspective," Abbey says.

Clinicians who treat or investigate autoimmunity increasingly are using personalized therapies to treat diabetes and other diseases, Sékaly says.

"I was involved in another protocol involving multiple sclerosis patients where they were depleted of their whole immune system and were reconstituted with a whole new system, using their own stem cells," Sékaly adds. "And that has been a very promising approach."

Eventually, clinical research into personalized therapies will evolve, but the challenge for clinicians and investigators is to make it a simpler process, he says.

"Personalized therapies aimed at the immune system will be the way to go," Sékaly says. "It will increasingly enter into the mold of regular therapies." Abbey agrees.

"We believe the best way to help these patients is by helping the patient's immune system to act the way it's supposed to act," Abbey says. "One of the huge advantages of these kinds of approaches is that they have very good safety profiles."

For both cancer and HIV drugs, the existing treatments have multiple side effects, but the early trials with the immunotherapy approach have not shown adverse events to be a significant problem, Abbey adds.

For instance, the process may result in a side effect from the injection of the drug, including some itching and minor discomfort, and it may result in flu-like symptoms with mild temperatures, but that's been about the extent of the adverse events discovered so far, says Lothar Finke, MD, chief medical officer and vice president, regulatory affairs, for Argos.

The type of procedures involved in the trials is complex and must be followed precisely, so there are challenges to both participants and investigators.

For instance, participants have to spend roughly half a day during the collection of their blood cells, and then there are five or six infusions of the vaccine product, Sékaly says.

"One of the biggest difficulties is ensuring that patients will not miss work or be penalized for missing work," Sékaly notes. "So we have tried to adapt the hours and process so it can be the least invasive to their schedule."

For example, the HIV clinical trial will schedule participants in the early morning or late afternoon, whichever is more convenient for them, he adds.

Investigators have to use a process called leukapheresis to harvest about eight billion white blood cells, which are a source of dendritic cells, without putting patients in an anemic state, Sékaly says.

"When we first told the IRB we were going to collect 10 billion white blood cells in HIV patients, we raised eyebrows," Sékaly recalls. "But when a patient undergoes this process, within the next 24 hours his white blood cells might dip slightly but, after 48 hours, everything goes back to normal."

Investigators had to convince IRB members that the process was safe, and it helped that they had safety information from the earlier cancer immunotherapy trials, he adds.

The HIV personalized immunotherapy trial is the first of its kind within the realm of HIV infection, Sékaly says.

"To my mind, as an immunologist, it makes a lot of sense, but for other people it's a concept that is completely new to them," Sékaly says.

Although CR in personalized immunotherapy is difficult for investigators to schedule and is time consuming for participants, if it's proven successful in the HIV trials, it could become an emblem of success in personalized medical research, Sékaly says.

Another challenge in personalized immuno-therapy will be the move to phase III trials, which may benefit from different trial designs and methodologies than what is employed by most phase III clinical trials.

Immunotherapy studies tend not to be neat fits with the Kaplan-Meier curve, Finke says.

"What happens with the treatment, very often, is below the 50% mark and is a so-called late effect," Finke says.

"In conventional study designs, whatever happens after the median mark is not recognized at all, so the statistics might ignore [positive results] completely," he explains.

There exists different approaches, including a statistical algorithm that recognizes the fact that chemotherapy and immunotherapy act differently, and so you have to apply different statistics to the conventional Kaplan-Meier methodology in order to account for that delay, Finke says.

If the phase II trials show strong positive data, then there will be momentum to carry the research to phase III trials, and these sorts of challenges will be overcome, Finke and Abbey say.