Oncolytic Virus Research Collaboration: Memgen Inc., UMichigan, and ALK Positive, Inc.
The ALK Positive NSCLC Research Acceleration Committee (RAC) systematically reaches out to selected biotech companies with NSCLC treatments in development and/or trial. In February of 2022, RAC member Ray Hall (father to patient Summer Farmen) wrote a letter to the CEO of Memgen Inc., introducing us and asking for a get-acquainted Zoom meeting, which occurred shortly thereafter. CEO Greg Brown, MD, MBA, and Chief Scientific Officer Mark Cantwell, PhD let us know that they were initiating a clinical trial at Duke and Moffit Cancer Centers for their oncolytic virus drug MEM-288 for patients with solid tumors, including lung cancer patients. The drug was developed in collaboration with Moffit, and Memgen holds a license for further development.
Oncolytic viruses are emerging therapeutics capable of both killing tumor cells specifically and stimulating anti-tumor immunity. MEM-288, Memgen’s oncolytic viral therapy, is engineered to both selectively target cancer cells and supercharge the immune system through expression of two unique and powerful immune modulators: the company’s proprietary CD40 ligand (CD40L) and the powerful cytokine interferon beta (IFNβ). In published mouse experiments, direct tumor injection of MEM-288 drove reduction of tumor growth within the injected tumor, and also reduced the size of distant metastases (Cancer Immunol Res 2023;11:466–85). This suggests that the treatment may be able to produce systemic anti-tumor (abscopal) effects. For ALK NSCLC patients, who typically do not respond to immune checkpoint inhibitor (ICI) therapies, if these results were to translate into successful in-human trials for ALK patients, then an alternative immunotherapy option would become available in addition to the current standard of care treatments with multiple tyrosine kinase inhibitors (TKIs).
A year after our Initial discussions, in March of 2023, the Memgen officers reached back out to Ray to schedule another meeting to review the early results of their Phase I Monotherapy Trial of MEM-288 in Advanced Metastatic Cancers Following Progression on Immune Checkpoint Inhibitors (which excludes almost all ALK NSCLC patients, who rarely respond to standard of care lung cancer ICIs). The study has now completed accrual with fourteen of the fifteen patients enrolled in this first-in-human study being NSCLC patients. The clinical results have demonstrated that MEM-288 is very safe with no dose limiting toxicity and only minor and transient (1-2 days) treatment-related adverse effects, like injection site reactions and flu-like symptoms. There was significant shrinkage of injected and non-injected tumors in four patients, which correlated with strong remodeling of the tumor microenvironment, infiltration of CD8+ T-cells (immune cells), and significant necrosis (cell death) and apoptosis (effect on distant metastasis) of tumor cells measured in tumor biopsies. Systemic immune activation was clearly noted in multiple patients in both tumor biopsies and peripheral blood following MEM-288 treatment. Two patients have had ongoing durable responses after completing MEM-288 treatment and then receiving follow-on salvage chemotherapy. Both had previously relapsed on the same regimens of chemo/immunotherapy prior to MEM-288. One patient has had a complete response greater than 9 months and the other a partial response. Mark Cantwell, Memgen’s CSO, noted, “We continue to follow these patients and implications for expanded avenues to use MEM-288 in combination with multiple therapeutic strategies.” Author’s note: All these individuals were likely hard-to-treat patients with advanced disease, having progressed on all standard of care options.
In the March 2023 meeting, Memgen’s officers also outlined plans to launch an expansion study testing MEM-288 in combination with an immune checkpoint inhibitor in NSCLC patients for whom first-line checkpoint inhibitor therapy had already failed. FDA clearance was received this June to proceed with the combination study. Note that MEM-288 is already an immunostimulatory agent, and by combining it with an immune checkpoint inhibitor, the hope is that the cancer killing affect will be multiplied, as was seen consistently in preclinical experiments across multiple tumor types. Prior ALK resistance considerations for ICIs are not thought to apply in this case, as the ICI will be further revving up an already activated immune response. Unfortunately, the trial design requires that patients have progressed on prior ICIs, thus again excluding ALK patients.
However, undeterred, and newly armed with Ken Culver’s (ALK Positive Director of Research and Clinical Affairs) slide deck, we pointed out that there are over 70,000 ALK NSCLC patients living in the U.S. alone now, and multiples of that number worldwide. We explained that each of us is eventually going to need an alternative treatment to TKIs, and that the field is wide open for a first-mover alternative. Additionally, many of us experience a series of recurrent tumors over the years on TKIs that could be injected with MEM-288 as a consolidative therapy, perhaps extending the timeline for TKI efficacy, and as an alternative for currently practiced surgery or targeted radiation. We also explained that many ALK patients have ongoing stable residual disease that may not be growing and could perhaps be treated with MEM-288 to potentially lower their overall tumor burden. These prospective patients for MEM-288 would be in addition to those for whom TKIs are relatively ineffective or are no longer working. RAC founder Colin Barton asked the question; why not test MEM-288 in combination with an ALK TKI? The Memgen execs were intrigued, but preclinical testing requires ALK positive mouse models, along with the specialized laboratory and scientists to do the experiments. Which brings us to the University of Michigan, and the Judith Tam ALK Lung Cancer Research Initiative.
In early 2022, the UMichigan ALK Initiative team began testing various drugs on ALK patient-donated tissue, and the ALK RAC members began introducing the UM scientists to biotechs with promising drugs for NSCLC. A few of the companies agreed to donate drugs to UMichigan, and subsequent testing is ongoing. One of those companies introduced was Memgen back in 2022. However, since MEM-288 is an immunotherapy drug, the donated patient tissue grown into organoids that UM was using does not possess the obligatory immune features to test an immunotherapy drug like MEM-288. But UMichigan’s immunology laboratory was in development, and came online earlier this year, complete with an array of ALK positive mouse models, mostly contributed by other research institutions where ALK patients are treated, that can be used to test immunotherapy agents like MEM-288.
So, in May of 2023 we brought the Memgen and UMichigan teams back together to discuss collaborative experiments of MEM-288 in ALK mice. The purpose of these experiments would be to translate potentially encouraging results into a clinical trial for ALK positive patients. It was decided that there would be four groups of mice: MEM-288 alone, TKI alone (probably alectinib), combination of MEM-288 and TKI, and control group. A budget was developed, the costs for UMichigan to perform the study were determined, an equitable split of those costs was offered by Dr. Sofia Merajver of UMichigan, and the parties agreed to proceed. Contractual arrangements are in process at this writing. The ALK Positive, Inc. board of directors approved a small contribution to the project on our behalf, so we are both a party to, and ultimate beneficiary of this effort. ALK Positive played a primary role in making this happen, and this newsletter article is an initial effort to generate awareness in the patient population about a promising clinical trial in the making, and hopefully on the horizon.
Presuming the preclinical evidence is positive, with Ray Hall’s expert assistance Memgen is thinking about an initial ten-patient, multi-site clinical trial with injections every three weeks for a total of six visits. With any luck, perhaps the tumors will not survive that long in some patients. Estimated ALK trial costs were discussed, and Memgen is being encouraged to apply for a grant through ALK Positive’s collaborative program with Lung Cancer Research Foundation, which recently kicked off with a two-million-dollar call for grant applications.
If and when this project does move into a trial phase, it will serve as additional proof of concept that ALK Positive, Inc. can indeed create clinical trials in the service of our own lifesaving mission. There are dozens of companies with promising NSCLC drugs in development that are not yet testing on ALK patients. We can change that.
Jeffrey M. Sturm BS, MA, MBA
Research Acceleration Committee Member
Clinical Trials Committee Member
Member Board of Directors
ALK Positive, Inc. www.alkpositive.org
Advisory Board, UofMichigan ALK Lung Cancer Research Initiative
Eight-year ALK NSCLC survivor