Cambridge Healthtech Institute’s Emily Le, PhD recently spoke with Fahar Merchant, PhD, President and CEO at Medicenna Therapeutics about his upcoming presentation “Tipping the Balance Towards Success in a Phase 2b Recurrent GBM Trial: Overcoming the Tumor and its Microenvironment by Targeting the IL4R Using MDNA55”, to be delivered at the Targeting Innate Immunity Congress.


Industry Profile: Medicenna Therapeutics

An interview with Fahar Merchant, PhD, President and CEO

Q. Why have you decided to be part of The Targeting Innate Immunity Conference?

Tapping into the innate immunity is an under-exploited area of immunotherapy. This conference provides an opportunity to bring this topic to the forefront, allowing a very timely and relevant discussion to take place especially as new areas in immuno-oncology take prominence. The conference program fits very well with our pipeline which is squarely focused on engineered cytokines such as IL-2, IL-4 and IL-13, which are key players in modulating the immune response either as super-agonists or super-antagonists, when targeting the tumor microenvironment (TME). In glioblastoma, an indication for which we just finished a Phase 2b clinical trial, innate immunity plays an important role as myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) make up as much as 40% of the tumor mass and may be a key factor as to why glioblastoma (GBM) is so aggressive and continues to be a uniformly fatal disease. Once diagnosed, 5 year survival is only 1 in 20 with most patients living only about 14 months. Following initial surgery, radiation and chemotherapy, the tumor inevitably recurs in all patients and the life expectancy in recurrent GBM (rGBM) is only 6 to 9 months. Our lead drug, MDNA55 has been tested in 112 rGBM patients in the US and Europe. It is designed to target the IL-4 receptor (IL-4R), a biomarker highly expressed in GBM and other brain cancers and is associated with a more aggressive disease and poor survival outcomes. Interestingly, IL-4R is also expressed by TAMs and MDSCs that make up the TME. So in a sense, we're able to do something quite unique because we can target both the tumor and also purge the TME, allowing the immune system to tackle the exposed malignant cells. As I mentioned, we have just recently finished enrolling for this trial and we see early evidence of improved survival in these patient. For example, we found that rGBM patients who over-express the IL-4R attain a median survival of 15 months following a single treatment with MDNA55 compared to 8 months historically. This is very exciting to us as this not only offers a significant benefit to this particular unmet population, but also offers hope for patients with at least 20 other solid tumors, and associated TMEs, where the IL4R is over-expressed.

Q. What is your company doing to move the industry forward in this space?

There is a need in the IO space to address barriers that prevent the immune system from eliminating the tumor. One of these barriers is the tumor-supporting microenvironment which forms a “cancer swamp” that is able to hide the tumor from the immune system. As long as you have this very insidious cancer swamp, it will be challenging to get to the tumor and improve cure rates. Shifting the TME from a Th2 to Th1 bias will be pivotal. This can be done by disrupting IL-4 or IL-13 signaling which together are critical to the development of Th2 immune responses associated with allergy, asthma, fibrosis and aggressive forms of cancer. MDNA55 and our modified IL-4 and IL-13 Superkines (MDNA413) can help tip the balance towards Th1 immunity by either purging the population of MDSCs and/or TAMs or blocking IL-4 or IL-13 activation of these cells. This would not only help treat patients with Th2 response-mediated diseases mentioned above, but can also transform aggressive cancers with a robust TME (“Cold Tumors”) to “Hot Tumors” making them susceptible to other cancer immunotherapies such as checkpoint inhibitors and cancer vaccines. Combination with rational targeted therapies such as bispecific antibodies, oncolytic viruses or BiTEs could then tip the balance in favor of the patient.

In addition to our MDNA55 program, we have an exciting early stage program being built around the IL-2 superkine, where we just announced our lead clinical candidate, MDNA19. MDNA19 is an engineered long-acting IL-2 which binds with high affinity to the CD122 receptor and potently stimulates effector T cells which attack the tumor while, unlike native IL-2, it does not bind efficiently to CD25 which is a pre-requisite to stimulate tumor protecting regulatory T cells. In preclinical studies we have combined MDNA19 precursor molecules with either an anti-PD-1 or anti-CTLA-4 checkpoint inhibitor and we see very dramatic cure rates in mice. The most exciting part is that when you re-challenge these mice on the opposite flank with the tumor, these tumors simply don't grow, showing that memory T cells have been generated. We believe that a potent CD122 directed IL-2 will be a prerequisite as a combination agent with other IO therapies, including checkpoint inhibitors, CAR T cells and oncolytic viruses.

Q. What do you think has changed the most in the IO space and what, in your opinion is the future outlook?

What is different today is the fact that we’re beginning to really understand and appreciate the tumor microenvironment and the many layers of immunosuppression that evolve to protect and prevent an immune attack on the tumor. Therefore, there needs to be a paradigm shift in the IO space to reconsider the strategy needed to treat cancers with immune-based therapies. We will have to find a sustained way to break down the tumor’s protective walls as well attack the tumor itself. Currently, many therapeutic strategies focus on boosting adaptive immunity against tumors. However, growing appreciation for the contributions of the innate immune response shows that there may need to be a synergy of both innate and adaptive immune effectors to give the most potent effect.

Another consideration is the heterogeneity of human cancers in general. This combined with the diversity of mechanisms acting together to suppress the immune response makes it unlikely that any single-agent immunotherapy will elicit meaningful tumor regression in a majority of patients, calling for the need for safe and efficacious combination strategies. This will probably involve combination with targeted therapies such as bispecific antibodies, oncolytic viruses or BiTEs could then tip the balance in favor of the patient.

But probably the most important consideration is cost and time. There has been some really high hopes around the CAR-T space, but the potential to be cost-prohibitive over the long term has led to the realization that we have to come up with something simpler in terms of manufacturing and accessibility. One of the things that is being contemplated is to include transgenes, such as superkines, into CAR T-cells or oncolytic viruses to boost selectivity and activity, which is an exciting space.

Time is also an important factor and wasting a cancer patient’s precious time on therapies that may not work for them is unethical. We can improve patient outcomes and health care costs if we are able to identify patients that are most likely to respond to treatment. As patients in our trial who have the IL-4 receptor was shown to have a median survival of 15 months following a single treatment with MDNA55 compared to 8 months historically, developing a companion diagnostic can help us identify patients that are going to benefit from MDNA55. I expect we will also be able do the same for other IO drugs, as there is a lot of work going on in the biomarker space.