Cancer cachexia affects the vast majority of cancer patients—up to 80% of late-stage patients—and directly causes nearly 30% of cancer-related deaths¹. In some cancers, such as pancreatic cancer, 70-80% of all patients experience some degree of cachexia². These statistics underscore how cachexia is such a prevalent and significant condition and emphasize the need for effective treatment options.

Beyond regarding cachexia as merely another unfortunate statistic associated with cancer, our team has strived to understand the personal implications of cachexia on patients and how our therapy might be regarded by the broader affected community, including patients, doctors, families, and the pharmaceutical industry. To these ends, we arranged discussions with cachexia and immunology experts and recorded podcast-style episodes of conversations with individuals directly impacted by cachexia.

Integrating what we learned from experts and personally affected individuals helped us hone the science guiding our project and identify ways to ensure our therapy will truly benefit cachectic patients.

Dane Wittrup, Ph.D.

Professor of Chemical Engineering and Biological Engineering, Massachusetts Institute of Technology

Click here to learn more about our conversation with Professor Wittrup.

We met with Professor Wittrup via Zoom on May 2nd. Prof. Wittrup's research focuses on tumor targeting and immunotherapies, so our goal was to understand how to create a therapy that localizes to the tumor or otherwise preferentially targets IL-6 in the tumor microenvironment. At the time, we intended to engineer T-cells to either sequester or degrade IL-6 specifically within the tumor. Prof. Wittrup helped us realize that reducing systemic levels of IL-6 is crucial to reduce cachexia symptoms, and also that despite T-cell therapy's popularity for other cancer applications, T-cells may not be the optimal cell type for us to engineer because they cannot sequester or degrade molecules. Additionally, Prof. Wittrup encouraged us to pursue degrading IL-6 rather than sequestering it because sequestration may only temporarily ameliorate the overabundance of IL-6 before ultimately exacerbating overproduction. Along those lines, Prof. Wittrup emphasized the importance of understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of the innate IL-6 signaling pathway and of our therapy. Thus, we kept the PK/PD profile of our therapy in mind during the design phase of our project, which is crucial for ensuring our therapy effectively heals patients with minimal negative side effects.

Teresa Zimmers, Ph.D.

Professor of Cell, Developmental, & Cancer Biology, Oregon Health & Science University and Research Scientist; President of the Cancer Cachexia Society

Click here to learn more about our conversation with Professor Zimmers.

We met with Professor Zimmers via Zoom on May 9th. As a leading advocate for cachexia research, Prof. Zimmers has a deep understanding of the biological underpinnings of cachexia along with the social and political factors affecting the state of cachexia research in general. She explained how, despite the fact that cancer is so well-known and thoroughly studied, cachexia is seldom considered by the public and even by researchers as a similarly pressing problem. For example, although monoclonal antibodies that sequester IL-6 exist and are used to treat other inflammatory conditions, such as rheumatoid arthritis, they have not been rigorously tested on cachectic patients because of a lack of interest and funding in cachexia studies. Our team has grappled with the fact that beyond just designing a therapy, much of the work necessary for treating cachexia involves raising public awareness and encouraging institutions to prioritize cachexia research. This motivated us to create our YouTube channel to spread information about the importance of cachexia and to create our podcast series to help experts' voices be heard.

Ishan Roy, M.D., Ph.D.

Assistant Professor of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine

Click here to learn more about our conversation with Dr. Roy.

We met with Dr. Roy via Zoom on May 16th. Dr. Roy is a practicing physician and research scientist who approaches cachexia from both a clinical and academic standpoint. In our conversation with him, we learned about the holistic approach doctors take when working with cachectic patients, from personalizing each patient's physical therapy to ensuring their dietician accounts for cultural traditions. This helped us contextualize how our therapy will fit in within a patient's overall cancer treatment program: rather than acting as a perfect monotherapy, it would serve as a crucial part of the broader set of regimens, activities, and drugs. Dr. Roy also raised an important point about the disproportionately low number of female patients in cachexia studies. Accordingly, our team has considered how our therapy may differentially affect males and females because the science informing it is based on primarily male data³. In particular, since the vast majority of clinical data is sourced from males, our therapy may be more likely to benefit males than females because of this bias; our therapy may nevertheless be effective for females as well, but ultimately the sex-based differences are very understudied. Finally, Dr. Roy explained how patients who undergo CAR T-cell therapy frequently experience extreme and sometimes fatal inflammation known as cytokine release syndrome (CRS); our therapy may be even more vital for CAR T-cell patients because it depletes IL-6, a key cytokine in CRS.

Lab of Dawn Bowdish, Ph.D.

Professor of Pathology and Molecular Medicine, McMaster University

Click here to learn more about our conversation with Dr. Bowdish's lab.

We met with Braeden Cowbrough and Kevin Zhao, members of Dr. Bowdish's lab via Zoom on June 26th. Dr. Bowdish's lab investigates the role of macrophages in the immune response. In particular, they analyze how macrophage phagocytosis changes with age and during acute and chronic inflammation, and how age-associated inflammation changes monocyte/macrophage development and function. From a technical standpoint, this meeting helped us understand how we should experiment on macrophages—in terms of precise protocols and equipment—and how our ultimate therapy might be delivered to patients for optimal functionality. Additionally, we discussed how our therapy's dependence on macrophages may mean that it affects patients differently depending on age. While we did not reach definitive conclusions because age dependence is an active area of research, we have factored this observation in to our overall goals and target demographic. In particular, we understand that our therapeutic may benefit younger patients more than older patients because functionality of macrophages tends to decline with age⁴.

Ron Weiss, Ph.D.

Professor of Biological Engineering, Massachusetts Institute of Technology

Click here to learn more about our conversation with Dr. Weiss and his lab.

We met with Dr. Weiss and his lab on June 28th, when we were generously provided an opportunity to present our project during the lab's Journal Club. Dr. Weiss is a pioneer in the field of synthetic biology, and members of his lab utilize genetic circuitry to advance programmable gene expression, transgene silencing, and more. Dr. Weiss provided constructive criticism on the design of our plasmids and future steps for improving the genetic circuitry to allow for modulation of IL-6 levels. Lab members, especially postdoctoral researcher Andrew Kane, also shared expertise on protein aggregation and how we can make IL-6 aggregation feasible. From another standpoint, presenting to the lab helped us hone our speaking skills and better understand our project; scientific communication is critical to ensuring that beneficial therapies reach audiences and create real impact, so practicing these skills was crucial for our project as a whole.

Jianzhu Chen, Ph.D.

Professor of Biology, Massachusetts Institute of Technology and the Koch Institute for Integrative Cancer Research

Click here to learn more about our conversation with Dr. Chen.

We met with Dr. Chen via Zoom on June 29th. Dr. Chen seeks to understand and take advantage of human immune system function in cancer immunotherapy and vaccinology, and his lab does so by leveraging computational, wet lab, and clinical tools to study immunological processes. Much of his research involves macrophage experimentation, and he provided valuable advice on how to work with macrophages in the lab and how to deliver drugs targeting macrophages. His broader research on immune function as a whole also helped us place our therapy in the context of a patient's entire immune system and helped us understand that our therapy may have off-target effects, both beneficial and harmful to the patient, that could be addressed down the road in the therapeutic development pipeline.

Episode 1: Ishan Roy, M.D., Ph.D.

Assistant Professor of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine

Click here to watch Dr. Roy explain how physicians carefully tailor treatment plans for cachectic patients.

Episode 2: Teresa Zimmers, Ph.D.

Professor of Cell, Developmental, & Cancer Biology, Oregon Health & Science University and Research Scientist; President of the Cancer Cachexia Society

Click here to watch Dr. Zimmers discuss advocacy and the social and ethical aspects of cachexia research.

On August 9th, our team presented a poster at da BOMB, more formally known as the Boston Mammalian Synthetic Biology Symposium. Da BOMB is an annual conference held at MIT's Koch Institute for Integrative Cancer Research that attracts nearly 200 local researchers and industry professionals with years of experience in synthetic biology. We had a wonderful time pitching our project and gaining valuable feedback from experts along with listening to talks on genetic circuitry, induced protein aggregation, and more. In particular, the talks covered not only technical aspects of state-of-the-art synthetic biology research but also emphasized how new discoveries are guided by the desire to truly help humans and thus must be carefully thought out in a human-centric manner. While presenting our poster, we received many questions and feedback about what we are doing to ensure CAR-P Diem will be most beneficial for patients, and we have since incorporated that feedback into our project by holding further conversations with cachexia experts and by rethinking the potential drug delivery system.

1. “Treating Cancer Cachexia: Progress Looks Possible.” National Cancer Institute, www.cancer.gov/about-cancer/treatment/research/cachexia.
2. Poulia KA, et al. "Pancreatic Cancer and Cachexia-Metabolic Mechanisms and Novel Insights." Nutrients. 2020 May 26. doi: 10.3390/nu12061543. PMID: 32466362; PMCID: PMC7352917.
3. Montalvo RN, Counts BR, Carson JA. "Understanding sex differences in the regulation of cancer-induced muscle wasting." Curr Opin Support Palliat Care. 2018 Dec. doi: 10.1097/SPC.0000000000000380. PMID: 30102621; PMCID: PMC6239206.
4. Roel P.H. De Maeyer, Emma S. Chambers. “The Impact of Ageing on Monocytes and Macrophages.” Immunology Letters, Elsevier, 10 Dec. 2020, https://doi.org/10.1016/j.imlet.2020.12.003.