New Treatment Offers Hope for Lupus Patients

By Dr. Eric Morand, Monash University, Australia

When real patients have unprecedented positive outcomes to a new treatment, it’s tempting to talk about it as “breakthrough” for medical science. This describes the excitement around a new report from researchers in Germany of a radical new treatment for lupus.

The patients in the study – five people with severe lupus – went into remission following pioneering CAR T-cell treatment, which uses genetically altered cells.

What is lupus, why is this such big news, and what could it mean for other patients and diseases?

Around 5 million people are affected by some form of lupus worldwide. The most common form of lupus is technically known as systemic lupus erythematosus. Though not widespread, it is more common than multiple sclerosis (MS). Both are “autoimmune” diseases where the immune system attacks its owner instead of the germs it is supposed to fight.

MS is an autoimmune disease where the immune system attacks nerve tissue. In contrast, lupus can affect any organ in the body. Treatments for lupus have been so poor for so long that even wealthy and famous people with the disease – like pop star and actor Selena Gomez – have had organ failure resulting in the need for a kidney transplant. A lot of complicating factors have made it hard to improve outcomes for people with the disease.

Firstly, the variety of tissues lupus can affect means no two patients are exactly alike. Diagnosis is hard and often delayed. This also means we researchers have to deal with a lot of complexity as we try to work out what is causing the disease. This clinical variability makes measuring improvement in response to treatment difficult, and many clinical trials have likely failed due to measurement issues.

Second, there is variation between patients in which part of the immune system goes wrong. This means different patients will need different treatments – and we still do not know with certainty how to get this right. But progress is happening fast.

Innate and Adaptive Immunity

The immune system is in two parts, innate and adaptive.

The “innate” immune system responds fast but non-specifically to viruses and other germs that hit the body with a slug of germ-killing inflammatory proteins. The “adaptive” immune system is slower but more precise. It swings into action after the innate immune system and provides long lasting defense against the invading germ.

When you are vaccinated against a disease (such as COVID), the fever and aches you might get in the first day or two is your innate immune system at work. But the long-lasting protection from antibodies is provided by a part of your adaptive immune system, a key part of which is delivered by cells called “B cells”.

In lupus, both parts of the immune system are involved, and both have been successfully used to develop medicines. Earlier this year, the Therapeutic Goods Administration approved anifrolumab, a drug which blocks “interferon”, a crucial protein made by the innate immune system.

Another drug which works on B cells of the adaptive immune system, called belimumab, was approved a few years ago. Unfortunately, neither drug is on Australia’s Pharmaceutical Benefits Scheme yet, so access is extremely limited.

However, we now know that interferon and B cells are both important, and so very strong treatments that almost completely eradicate either could be useful. That is where this potential new treatment comes in.

Already Used to Treat Cancer

Treatments to destroy B cells are used in cancers like lymphoma. The most powerful of these uses CAR-T cells, which train a type of natural cell to be an assassin of the B cell.

CAR-T medicines are highly complex to make, and extremely expensive – but they work.

T cells are collected from the blood, then re-engineered in a special laboratory.

Now, this new report shows targeting B cells using this approach could be effective in lupus too. Building on a first-ever patient treated in this way by the same group a year ago, doctors in Germany created a “homemade” CAR-T treatment and used it in five patients with severe lupus.

Remarkably, all five patients had near complete eradication of disease, allowing them to stop conventional medicines, like steroids, with potentially harmful side effects.

What This Means for Other Patients

So what does it mean for patients in Australia? Well, most centres aren’t able to make their own CAR-T treatments, so delivering this potential treatment will require a commercial approach.

However, it might be quicker to market than other treatments in development as it takes a proven approach into a new disease, rather than being new from the ground up.

One day we might even be able to extend such treatments to other autoimmune diseases, like MS, where B cell-directed treatments have been helpful, as well as in lupus.

This would need to be balanced against risk. Importantly, short term side effects of CAR-T treatment (which include brain and bone marrow problems) can be severe. For this reason, such a treatment would only be used for the most severe cases in which standard treatments have failed, like the patients in the German trial.

Long-term side effects are also unknown at this time, and of course suppressing the immune system so profoundly in the setting of a pandemic is not without major risks.

Formal trials of a commercial CAR-T medicine for lupus are in the advanced planning stages already, and Australia is likely to be front and centre of these due to our lupus expertise and trial-friendly regulatory environment. With all these advances, we can at last tell our patients, and our friends and family with lupus, that there is light at the end of what has been a very long tunnel.

Eric Morand, MD, is a clinical rheumatologist and Head of the School of Clinical Sciences at Monash Health, Monash University in Australia.  Dr. Morand consults with companies involved in lupus drug development, including Novartis and AstraZeneca. He receives funding from Australia’s National Health and Medical Research Council and Lupus Research Alliance US, and is a Director of Rare Voices Australia.

This article originally appeared in The Conversation and is republished with permission.

A Promising Stem Cell Therapy for Back Pain

By Gabriella Kelly-Davies, PNN Columnist

Just before sunrise on Christmas Eve last year, a delivery van from our local fish market left a bulky box of fresh prawns, oysters and lobsters on our doorstep for Christmas Day celebrations.  

Sleepily bending over, I picked up the box, unaware it was packed to the brim with enormous blocks of ice to prevent the seafood from succumbing to Australia’s stifling summer heat. As I lifted the box from the doormat, I felt a sharp pain like an electric shock run down the back of my left leg and pins and needles explode in my left foot.  

Fast forward to now, and the pain and pins and needles sensation are constant, especially when I sit to write. Like millions of other people, I have chronic lower back pain, the leading cause of disability worldwide. And like them, I too want the pain to go away without surgery.  

Two weeks ago, my pain specialist injected cortisone into my spine, reducing the pain enough to allow me to sit for meals and do a little writing. But he warned I would most likely need surgery at some point. The neurosurgeon agreed, suggesting microdiscectomy was my only option.  

As a former physiotherapist, I know that a lumbar discectomy can relieve the symptoms of nerve compression, but it doesn’t reverse the underlying degeneration of the intervertebral disc. This is why up to one third of patients continue to experience back pain after surgery and some require further operations.

In my search for non-surgical treatments, I read an article about Australian research that has led to the development of a new stem cell therapy to treat back pain. Professor Tony Goldschlager, who leads the study, is a neurosurgeon who advocates for the use of minimally invasive spinal surgery. He heads up a research team at Monash University in Melbourne that is part of the Monash Health Translation Precinct (MHTP).  

Goldschlager started his stem cell research 15 years ago. He and his team developed the stem cell therapy in the laboratory, then spent years testing it in preclinical models. The results of several studies revealed that the therapy was safe and effective. After completing these studies, the researchers began human clinical trials, testing the ability of stem cells to regenerate the intervertebral disc and reduce back pain.  

“We’ve had success both in preclinical and clinical studies of being able to restore structure and function of the disc,” Goldschlager told me. “This reduces pain and improves quality of life for patients.” 

Phase Two clinical trials saw a significant number of patients report reduced back pain for up to two years after a single injection. Phase Three trials are almost complete and while Goldschlager hasn’t received all the results from overseas studies, the data he has seen so far is promising. He is hopeful the new treatment— a single injection — will be available in two years after the final round of clinical trials concludes. 

“What excites me is that we might be able to prevent surgery all together and regenerate the disc. Most of the current treatments don’t address the underlying problem. But the stem cell injection reduces the inflammation and stimulates a regenerative process in the disc, removing the source of back pain. The stem cells can become new disc-like cells and replenish the damaged disc cells,” explained Goldschlager. 

During the last 15 years, Goldschlager and his team have published the results of their studies in peer-reviewed journals such as Spine, Nature Outlook and the Journal of Neurosurgery. In 2015, they published an extensive review of the use of stem cell therapies in lumbar disc disease. 

New Era in Medicine

While the use of stem cells heralds the dawn of an exciting new era in modern medicine, it also raises several ethical and safety concerns. Critics say many stem cell therapies are unproven, and others believe it is unethical to destroy human embryos during research or create new embryos specifically for research. 

Goldschlager is acutely aware of these concerns and in 2010 as a neurosurgery registrar, worked in a research team that published an article on the ethics of using stem cell therapies in patients with spinal cord injuries. He says the therapy his team has developed doesn’t raise ethical concerns because it is based on a proprietary adult stem cell technology from Mesoblast, an Australian biotechnology company.

The cells are derived from the bone marrow of healthy young adults who have given informed consent. Young adults are selected because the number of stem cells in our bodies reduce as we age. The cells of older people are also less effective at repairing damaged tissues and organs.

Commercial stem cell clinics usually harvest the fat, muscle or cartilage cells of their patients, process the cells in a centrifuge, then inject them back into the same patient’s body. This yields a mixed population of cells with a small and inconsistent number of stem cells. Adults of all ages are offered this treatment, even though it might not work for older patients because their stem cells are not as plentiful or robust as those of younger ones. These treatments can cost thousands of dollars, are often ineffective, and come with a heightened risk compared to a pure, tested proprietary off-the-shelf product.  

Another reason for caution is that some of the clinicians who provide stem cell treatments lack sufficient training and accreditation, increasing the risk of safety and efficacy issues. It is critically important for patients to check the qualifications of clinicians who offer stem cell therapies and to understand how the cells used at these clinics are created. The therapy should have been through rigorous clinical trials to demonstrate safety and efficacy.  

While new stem cell treatments offer hope to millions of people who live with degenerative spinal conditions, they are not a “miracle cure.” Still, I hope I’ll have the option of trying Professor Goldschlager’s technique once it is available.

Gabriella Kelly-Davies lives with chronic migraine.  She recently authored “Breaking Through the Pain Barrier,” a biography of trailblazing Australian pain specialist Dr. Michael Cousins. Gabriella is President of Life Stories Australia Association and founder of Share your life story.

Research Uncovers Why Some Pain Meds Don’t Work

By Pat Anson, Editor

An international team of researchers may have discovered why some pain medications are inneffective: they target receptors on the surface of nerve cells that have moved out of reach.

Their findings, published in the journal Science Translational Medicine, may lead to the development of a new class of pain medication that is more potent and less prone to side effects than opioids and non-steroidal anti-inflammatory drugs (NSAIDs).

"Opioids and NSAIDs do not work for everyone and have unacceptable side effects, particularly when used over a long period of time," said Nigel Bunnett, PhD, a professor of surgery and pharmacology at Columbia University Medical Center.

"However, previous efforts to develop more effective analgesics have been stalled by our limited understanding of the mechanisms that allow nerves to sense and transmit pain signals."

Many pain medications work by targeting protein receptors on the surface of nerve cells that transmit pain signals. One receptor – known as the neurokinin 1 receptor (NK1R) -- causes pain and inflammation when activated.

In a series of laboratory experiments on rodents, Bunnett and his colleagues discovered that NK1R, when stimulated by pain, quickly moves from the cell surface to inside the cell membrane, where it continues to function outside the reach of pain medication. Researchers found that when they added a lipid (fat molecule) to painkillers that can cross the cell membrane, they effectively blocked NK1R and provided potent and durable pain relief to the rodents.

"From these experiments, we have demonstrated that designing NK1R inhibitors that are capable of reaching the endosomal network within nerve cells may provide much longer-lasting pain relief than currently available analgesics," said Bunnett. "We think that modification of many existing compounds, as we did with NK1R inhibitors, may have the potential to enhance the effectiveness of many different classes of medications."

The next step for researchers is to see if the same results can be found in humans. If proven, it could mean that current pain medications could be redesigned to make them more effective.

"This is a proof-of-concept study that shows that we can re-engineer current pain drugs and make them more effective. The challenge is now to translate the technology into human clinical trials. This is a complex and challenging path – but the ultimate benefits to patients with nerve pain are potentially highly significant," said Dr. Meritxell Canals of Monash Institute of Pharmaceutical Sciences at Monash University in Australia.

The study was supported by grants from Australia’s National Health and Medical Research Council, the Australian Research Council, and Takeda Pharmaceuticals.