Innate Responses

There are two parts to the human immune system: adaptive and innate. There are many therapies designed to improve the adaptive immune response against cancer (for example, vaccines, CAR-T cells and immune checkpoint inhibitors), but far fewer efforts focus on boosting the innate immune system response to cancer. According to Inmune Bio CEO, RJ Tesi, if medical practitioners only have access to therapies targeting the adaptive immune system then it’s like trying to fight with just one hand... Tesi wants to bring the innate immune system into the ring. We asked him more about the company’s research.

What inspired this approach to treating disease?

Early in his career, our founder, Mark Lowdell, determined that NK cells – not T cells – are responsible for eliminating minimal residual disease (MRD). Cancer relapse, the disease that kills the most patients, is caused by MRD. At the time of his discovery in the late 1990s, this finding was considered very controversial, but today it is well accepted – and attempts to improve NK cell function are gaining traction in the clinical and drug development community. Inmune Bio was founded on INKmune, our first program, but we haven’t stopped at NK cells. Both microglial cells, the immune cells of the brain, and myeloid derived suppressor cells (MDSC, the cells that protect cancer from immunotherapy) are part of the innate immune system. We have been targeting microglial cells and MDSC with Xpro1595 and INB03 respectively in an attempt to treat Alzheimer’s disease (AD) and cancer.

How far have you gone down the translational path?

All our programs are in phase I. The INB03 program in cancer is enrolling patients and the Xpro1595 program for AD is screening patients for the trial. We hope to enrol the first patient soon. The INKmune program will be enrolling patients in the fourth quarter of 2019. By the end of the year, we will be enrolling patients in three phase I trials!

Why do you think this approach is a promising avenue for fighting Alzheimer’s?

AD and dementia are caused by nerve cell death and synaptic dysfunction. Without synapses, nerve cells cannot communicate. Even if you have good nerve cells, if there is synaptic dysfunction then you will get dementia. Synaptic dysfunction means weaker, fewer or otherwise malfunctioning synapses. Neuroinflammation is caused by activated microglial cells, which secrete inflammatory cytokines that kill nerve cells and cause synaptic dysfunction. The “master” cytokine is soluble TNF (sTNF) – this is the main cause of nerve cell death and synaptic pruning. Xpro1595, a second generation highly selective inhibitor of sTNF, targets sTNF (the bad TNF), while leaving trans-membrane TNF (the good TNF) intact. I think this unique pharmacology separates it from currently available non-selective TNF inhibitors that block both the good and bad TNF. Xpro1595 has been shown to reverse the symptoms of AD in animal studies. Our data with Xpro1595 was so impressive that Alzheimer’s Associated gave us a $1 million grant under its Part the Cloud to RESCUE initiative, which aims to accelerate the transition of research into clinical practice.

Other than animal data, we have other hints that targeting sTNF is a great way to prevent AD. Patients with rheumatoid arthritis (chronic inflammation) have an eight-fold increase in the risk of AD compared to other patients, unless they have their rheumatoid arthritis treated with a TNF inhibitor. Patients treated with anti-TNF therapy have a lower risk of AD compared with other patients! This confirms that TNF is a target.

Unfortunately, all is not good. As currently available TNF inhibitors block both sTNF and trans-membrane TNF, there are increased risks of infection, cancer and multiple sclerosis. Thus, they trade one disease for another. The advantage of Xpro1595 therapy should be that the patient gets all the advantages of targeting TNF without the serious side effects.

How are you approaching the challenge of clinical translation?

Translation from mouse to man is a scary problem for small biotech companies like ours… We attempt to manage risks in two ways. The first is to identify the subset of patients that will respond to our treatment – and to not presume that every patient with a diagnosis has the “type” of disease that could be treated by our therapy. For example, the patients we enrol in the AD trial will be selected for patients who have inflammation as part of their disease. This means we have a very good chance of selecting patients with microglial activation as part of the pathophysiology driving their disease. Ultimately, this is about precision medicine; improving the chances that you will include patients that will benefit from therapy and exclude patients who will not benefit from the therapy. This is good medicine.

Our second strategy is to use biomarkers of drug effect to ensure our drug is doing what it is supposed to do. For instance, after patients are treated with INKmune, we expect their NK cells to be able to kill cancer cells. We have a simple bioassay that should demonstrate that INKmune therapy is doing what it is supposed to be doing – priming the patient’s NK cells to kill their cancer.

What are the company’s plans for the remainder of 2019?

Our primary goals are to get patients enrolled into the XPro1595 trials. One thing drives value – clinical data! And we spend every hour of every day thinking about how to move our programs forward!