I M PA C T R E P O R T
2023
Technology Making "Founded in 2010, the Dana-Farber Accelerator helps translate scientific inventions made by Institute scientists into therapies, diagnostics, and clinical care technologies to benefit patients and their families around the world. Since inception, and enabled by generous philanthropic support, the Accelerator has awarded more than $6.6 million to Dana-Farber teams to improve the odds of successfully bridging the gap between the Mary Tolikas, PhD, MBA laboratory and the clinic. SVP & Chief Innovations Officer In 2023, the Accelerator adopted an approach that integrates exciting and Christiana Iyasere, MD, MBA Senior Director Accelerator promising science with intellectual property and business development strategy. This allows us to be agile and dynamic in effectively addressing key questions and challenges, as technology development proceeds within the rapidly evolving oncology landscape. By bringing to bear the diversity and wide range of our colleagues’ expertise at Dana-Farber, as well as collaborations and partnerships with faculty, clinicians, industry, the business/VC community and the government, we continue to strengthen our understanding and efforts across all aspects of technology translation: scientific, business, legal, regulatory and clinical. This report highlights the projects funded by the Dana-Farber Accelerator in the 2022/2023 cycle and hence, speaks to some of the exciting science coming out of Dana-Farber and its potential for impact. We thank the Dana-Farber community and donors for a successful year and look forward to the months ahead with unwavering commitment to the Dana-Farber mission and core values." Sincerely, Christiana Iyasere & Mary Tolikas
an IMPACT
Accelerating drug development with PhAST antibody discovery (pg 4)
Empowering natural killer cells to seek and destroy (pg 10)
Fast and furious: Next generation targeted protein degradation (pg 14)
Double the Impact: Dual targeted CAR T-cells against multiple myeloma relapse (pg 6)
Unlocking the immune system as a sensor for early cancer detection (pg 8)
Restoring the guardian: p53 tumor suppression without toxicity (pg 12)
2023 Awardee
Accelerating drug development with PhAST antibody discovery Antibodies that target specific tumor-expressed antigens are now the standard of care for some cancers. However, the identification of new proteins that are differentially expressed on tumors and are amenable to antibody binding remains challenging. To address this bottleneck in developing new antibody-based drugs for solid tumors, a team led by Prof. William Hahn, MD, PhD, executive vice president and chief operating officer at Dana-Farber, and Bärbel Schröfelbauer, PhD, lead scientist, Cancer Surface Profiling, developed the PhAST (Phenotypic Antibody and Simultaneous Target)discovery platform, for the high-throughput, unbiased, simultaneous discovery of therapeutic antibodies and their targets.
TEAM
William Hahn, MD, PhD
Bärbel Schröfelbauer, PhD
Sarah Hill, MD, PhD
Prafulla Gokhale, PhD
“The PhAST platform integrates much of what researchers have learned in the past 40 years of therapeutic antibody development and combines it into an integrated way of finding antigens and antibodies at the same time,” says Dr. Hahn. It allows for the unbiased discovery of hundreds of antibody/target pairs selective Research within the Hahn laboratory Source: Sam Ogden/Dana-Farber
for any cancer type of interest through a single round of screening. Instead of many months to discover antibodies against a single target, the PhAST platform allows for the discovery of many targets and antibodies in parallel, shortening the previously lengthy process to two to three months. The PhAST platform has led to the discovery of various new targets in ovarian cancer, which, at stage IV, has a five-year survival rate of only 30.8%.
Antibodies binding to target antigens. Source: selvanegra/Getty Images
Among these targets is BCAM, a protein that is highly expressed on the surface of high-grade serous ovarian cancer cells
and has been shown to be involved in adhesion and migration of carcinoma cells. In parallel to BCAM, a PhAST screen identified 37 fully human antibodies targeting it. With Accelerator funding, the research team is expediting the development of some of these novel antibodies, by enabling in vivo studies, a critical step towards translating the technology to humans. Other contributors to the project include Prof Sarah Hill, MD, PhD, physician scientist in the Department of Medical Oncology and Division of Molecular and Cellular Oncology and Prafulla Gokhale, PhD, director, Experimental Therapeutics Core at Dana-Farber.
2023 Awardee
Double the Impact: Dual targeted CAR Tcells against multiple myeloma relapse
TEAM
Multiple myeloma is a plasma cell cancer for which we still lack cures. Despite many advances in immunotherapies that result in high overall response Eric Smith, MD, PhD rates, relapse is a common occurrence. This year, the Accelerator supports a new strategy to induce long-term remission – perhaps even cure in some patients — based on dual-targeted CAR T-cell Anusuya M. Ramasubramanian, PhD therapy which uses a patient’s own engineered T cells to specifically target cancer cells. Developed in the lab of Prof. Eric Smith, MD, PhD, director, Translational Research, Immune Effector Cell Therapies at Dana-Farber, the goal of this technology is to eradicate all myeloma cells including those almost always left behind that lead to relapse in nearly all patients. In current myeloma treatment, approved CAR T-cell therapies target single antigens such as B-cell maturation antigen (BCMA), or, in previous work from Dr. Smith’s team, targeting
The Smith lab genetically manipulates cells for therapeutic purposes, including treatment of multiple myeloma Source: Getty Images/elkor
GPRC5D (G-protein-coupled receptor family C group 5 member D), that has been tested in first-in-human clinical trials. The goal is to create a CAR that targets two different myeloma antigens to enhance the success of CAR T-cell therapy targeting only BCMA. The impact would be to get multiple myeloma patients into deep remissions and hopefully cure some of them.
Illustration of CAR (chimeric antigen receptor) T cell immunotherapy. Source: Keith Chambers/Getty Images
“The Accelerator funding will expedite the selection of lead CAR T-cell candidates that will ultimately be tested in clinical trials,” says Dr. Smith. Generating and screening CAR T-cell libraries along multiple parameters, including cytotoxicity and persistence, is essential to the identification and development of clinically translatable cellular therapies. Joining the effort is Dana-Farber’s IMPACT2 (IMmunotherapy Platform for Antibody and CAR Therapeutics discovery and Translation) team, headed by Anusuya Ramasubramanian, PhD.
2023
2023 Awardee
Unlocking the immune system as a sensor for early cancer detection
TEAM
A collaborative team from Dana-Farber has developed a new platform for immune cell profiling to enable earlier, more accurate and easier diagnosis and prognosis for patients with multiple myeloma.
Irene Ghobrial MD
Grown out of a research collaboration between Kenneth Anderson MD, PhD Dana-Farber investigators Prof. Irene Ghobrial, PhD, director, Clinical Investigator Research Program and Lavine Family Chair for Preventive Gaddy Getz, PhD Cancer Therapies, Prof. Kenneth Anderson, MD, director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, and Romanos Sklavenitis-Pistofidis, MD, PhD, Romanos Sklavenitis-Pistofidis, MD, PhD Department of Medical Oncology, along with Prof. Gad Getz, PhD of the Broad Institute, the tool taps into the immune system as a sensor for detecting multiple myeloma and identifying the most effective treatment for patients. Traditional diagnostic tools for multiple myeloma include bone marrow biopsy and FISH (fluorescence in situ hybridization), both of which fall short of meeting the needs of both clinicians and patients. FISH, a method for pinpointing disease-contributing genes, has a 30-50% failure rate, overlooking crucial genome aberrations pivotal for guiding therapy. Bone marrow biopsy, marked by its discomfort and inconvenience, necessitates repeated procedures after relapse, subjecting patients to a cycle of 10-15 biopsies in a lifetime.
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SPARK Award
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The new platform hinges on whole genome sequencing of circulating tumor cells and single-cell sequencing of immune cells isolated from blood samples. This approach offers improved accuracy in diagnosing and predicting the prognosis of multiple myeloma compared to FISH and biopsy. While the FDA has approved over 20 drugs for multiple myeloma, the lack of a precise bloodbased method to match patients with appropriate treatments remains a critical gap, including therapy for some of the Microscopic view of multiple myeloma stained cells. Source: MD Saiful Islam Khan/Getty Images
latest promising drugs like bispecific antibodies and CAR T therapies. This platform identifies patients with specific genomic alterations unlikely to respond to such treatments, thus sparing them undue toxicity. Accelerator funding is supporting critical steps in the validation of the platform, enabling the creation of detailed reports for both diagnosing disease and predicting disease outcome from a single blood sample. “By deeply understanding changes in the immune system, we can define patients who may respond to immunotherapy or even identify cancer early,” says Dr. Ghobrial. “This platform has profound potential for clinical diagnostic benefit, and importantly can also be used to identify novel targets and prioritize them for future therapeutic discoveries.”
2023 Awardee
2023
Empowering natural killer cells to seek and destroy As their name implies, natural killer (NK) cells are immune cells with an intrinsic propensity to kill cancer cells and are of high interest in the cancer immunotherapy field. However, they can’t always get into the tumor microenvironment to do the job, particularly in solid cancers. One strategy for boosting the effect of NK cells is to create what are called NK-chimeric antigen receptor (CAR) therapies, or NK-CARs, to get NK cells to cancer cells and destroy them. CAR therapies work by genetically altering a part of the immune system to fight cancer.
Dr. Rizwan Romee in the lab. Source: Sam Ogden/Dana-Farber
SPARK
TEAM
Rizwan Romee, MD
David Barbie, MD
Mubin Tarannum, PhD
The Accelerator is funding a new NKCAR approach from the laboratories of Assoc. Prof. Rizwan Romee, MD, director, Haploidentical Donor Transplantation Program, and Assoc. Prof. David Barbie, MD, associate
director, Robert and Renée Belfer Center for Applied Cancer Research. The technique is aimed at improving the cancer-seeking and killing ability of NK-CAR therapies by harnessing the properties of the STING — or stimulator of interferon genes — pathway that naturally attracts NK to cancer cells. “Our novel genetic manipulation allows us to create what are
Award
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Live (blue) and dead (red) cancer cells after treatment with an engineered NK cell therapy. Source: Elena Ivanova/Dana-Farber
‘STING seeker’ NK cells and NK cell CARs which are much better at gaining entry to tumors and killing solid tumors,” says Dr. Romee. Currently, STING agonists need to be injected directly into tumors, representing a particularly obvious dilemma in the face of metastatic disease.
This new approach is based on the hypothesis that exogenous STING agonists are not necessary to trigger STING activation. Instead, the team’s approach is to take advantage of the STING mechanism by genetically modifying NK cells into STING seekers. The improved NK-CAR therapies should reach cancer cells more easily, survive longer in the harsh tumor microenvironment, and lead to better cancer cell death. Contributions from Mubin Tarannum, PhD, post-doctoral fellow and Romee lab manager allowed the team to test the activity of the engineered NK cells in various in vitro and in vivo cancer models. Moving forward, with Accelerator support the researchers plan on new studies in mouse models of some of the toughest solid cancers to treat, including lung (mesothelioma and NSCLC), ovarian, and pancreatic tumors. They will evaluate the modified NK-CARs alone and in combination with a STING agonist. The team also plans on investigating their modified NK-CARs in patientderived organoids – cultures of tumor cells derived from patients – that mimic the biological characteristics of real human tumors.
2023 Awardee
Restoring the guardian: p53 tumor suppression without toxicity
TEAM
p53 remains the best-studied and most common tumor suppressor gene, but the gene is mutated in half of all tumors rendering its activity useless in Dipanjan Chowdhury, PhD stopping cancer growth. For decades, researchers have sought to increase p53 activity. Results in the field have thus far been disappointing, largely due to David Scott, PhD toxicity mediated by efforts to restore p53 activity via small molecule approaches. However, the team of Prof. Dipanjan Chowdhury, PhD, chief, Division of Radiation and Genome Stability and Svanberg Family Sirano Dhe-Paganon, PhD Chair, David Scott, PhD, director, Medicinal Chemistry Core, and Sirano Dhe-Paganon, PhD, director, Structural and Chemical Biology Center at Dana-Farber have a new approach supported by the Accelerator — developing small molecule inhibitors of Tudor-interacting repair regulator protein (TIRR) to be used in patients with tumors that retain at least one copy of wild-type p53. The most well-studied approach for restoring p53 has been by inhibiting the MDM2 protein. However, clinical trials of at least ten MDM2 inhibitors show that while they increase p53 levels, that increase has been too toxic for the body. Therefore, the identification of targets that activate p53 without boosting their levels remains a competitive area of drug discovery and one with potentially significant promise in treating many cancers. Several years ago, Dr. Chowdhury and his team discovered TIRR, a novel p53-associated protein, but they were not aware of its mechanism of action on p53 at the time. Since then, the team discovered that TIRR inhibition
activates the tumor suppressor functions of normal, wild-type p53 leading to cancer cell death. Since half of all cancers retain at least one copy of wild-type p53 this therapeutic strategy may be widely TIRR structure. Source: Botuyan 2018, NSMB.
applicable to multiple tumor types, and a potential approach that avoids the toxicity seen with previously developed MDM2 inhibitors. The researchers found that TIRR affects selective functions of the gene such that it is not harmful to normal cells. Studies in TIRR-knockout mice revealed increased p53 activity but the animals showed no signs of toxicity. Since then, Chowdhury and colleagues have identified and validated TIRR as a new therapeutic target. “Activating p53 has been the holy grail of cancer drug discovery,” says Dr. Chowdhury. “If we can activate this powerful tumor suppressor without altering protein levels, we should be able to suppress a wide variety of tumors. We are cautiously optimistic that TIRR inhibitors will upregulate p53 without toxicity.” Accelerator funding will help the team make chemical compounds targeting TIRR. Already, multiple hits for chemical matter have been identified through small molecule library screens and the team is optimizing the chemical starting points into potent and selective TIRR inhibitors.
2023 Awardee
Fast and furious: Next-generation targeted protein degradation Technology developed within the laboratory of Asst. Prof. Xin Zhou, PhD, of the Department of Cancer Biology at Dana-Farber capitalizes on the unique metabolic demands of cancer cells: their requirement for elevated levels of iron for rapid growth and spread. The approach relies on the concept of targeted protein degradation (TPD), an area of intense interest in drug discovery.
TEAM
Xin Zhou, PhD
Pasi A. Jänne, MD, PhD
TPD works by removing specific disease-associated membrane-bound proteins from the surface of cells, many of which cannot be targeted and inhibited with traditional methods. The degradation approach offers a new way to entirely capture these previously ‘undruggable’ targets by internalizing them inside the cell where they – and the cancer cell – are destroyed. The technique reduces the toxicities associated with many other cancer treatments which often harm healthy tissue. At the heart of Dr. Zhou’s innovation is a technology known as Transferrin Receptor Targeting Chimeras (TransTAC), which are bispecific antibody molecules that leverage the natural behavior of the transferrin receptor – a pivotal protein overexpressed on the surface of cancer cells. Two membrane proteins brought together by a heterobispecific antibody. Source: Kaitlin Rhee/Dana-Farber
Found in abundance in several cancers, the transferrin receptor shuttles iron molecules into cancer cells, then quickly returns to the cell surface for another round. This process occurs at a rate of 500 receptors per second, fueling the rapid growth of cancer cells by aiding iron uptake. TransTACs repurpose this naturally recycling receptor for targeted protein degradation by coupling an antibody binder to the receptor with another antibody engineered to target a specific cancer protein of interest. Examples include EGFR, PD-1, or CD20 – well-known proteins that are overexpressed in different cancer types. One arm of the TransTAC homes in on the transferrin receptor on cancer cells while the other arm selectively binds to the target protein. The transferrin receptor, along with the tethered target, enters the cell. Dr. Zhou’s molecular design ensures that the target protein stays inside the cell where it will be destroyed while the transferrin receptor recycles. Critically, because tumor cells make more of the receptor than healthy cells, the approach improves the potential for avoiding the destruction of normal cells. The innovation’s potential has been validated through the successful testing of multiple TransTAC degrader molecules, including an EGFRtargeting TransTAC for lung cancer developed in collaboration with Prof. Pasi Jänne MD, PhD, director, Lowe Center for Thoracic Oncology and director, Belfer Center for Applied Cancer Science. The technology’s efficiency in degrading a diverse range of cancer membrane proteins establishes new possibilities for targeted precision cancer therapy. Accelerator funding will enable Dr. Zhou and her team to develop additional TransTAC specific binders and enhance the overall IP portfolio of the technology.
The Accelerator
2023
Translational Science Improves Clinical Care
The Accelerator is focused on the translation of scientific discovery from DFCI investigators into first in class technologies with the potential to create significant impact in the healthcare community. We identify primary investigators taking on high risk science that with critical funding and mentorship can efficiently move their project along a translational development pathway towards commercialization. Accelerator monies are focused on key developmental inflection points that pressure test assumptions and answer critical questions about the ability of the potential technology to translate into a therapeutic or diagnostic for patients with cancer. Through collaboration we can align technical, business and intellectual property strategies to enable subsequent partnering of successful projects with the best partner to further the next stage of development. Our work is just one step in a long journey from translational science to improved clinical care.
An Integrated Strategy Successful development of nascent technologies requires a multidisciplinary approach that takes into account the unique opportunity presented by the technology, integrating in-depth understanding of the translational science, the relevant competitive landscape into which the technology will be introduced, and an intellectual property strategy that strengthens the business case, all with a focus on maximizing the potential impact of the technology. To be able to do such work the Accelerator draws upon the diverse expertise of the DFCI community to support projects. IP Strategy
Impact Tech Development
BD Strategy
Importantly, the Accelerator team operates out of the Belfer Office of Dana-Farber Innovation (BODFI), a group of business development, licensing, and contracts professionals whose collective mission is to expedite the translation of the discoveries made in the labs at DanaFarber. To make this all work requires a dedicated collaboration between the primary investigator, the Accelerator team, the larger BODFI Office and DFCI Office of General Council to create and hone an effective strategy for technology development.
The Accelerator
2023
Adding Value at the Right Preclinical Stage DISCOVERY
PRECLINICAL
CLINICAL
Diagnostics
Early Discovery & Development
Target Validation
Analytical Validation
Preclinical Research
Clinical Research
Therapeutics
Early Discovery & Development
Target Validation
Hit to Lead
Lead Optimization
Clinical Research
One of the most challenging points in the development of novel technologies for academic investigators is advancement along a preclinical translational paradigm, pushing scientific inquiry from a series of observations made in the lab to a set of testable experiments focused on creating a technology with clinical utility. In early therapeutic development these next steps often involve target validation, high-throughput screening for potential compounds of interest, and testing the technology in a live model – known as in vivo proof of concept. For diagnostics, moving from an identified biomarker with predictive ability to a diagnostic tool with both analytic and clinical validity is a significant challenge, both in determining the necessary experiments to demonstrate the technology works and understanding the clinical paradigm in which the diagnostic will impact clinical care. The Accelerator program provides financial support and requisite expertise at these crucially important junctures, an area where traditional funding sources often fall short. SPARK awards fund 12 months of Accelerator enablement focused on lab experiments that can quickly determine if a project has the potential to move forward as a promising technology.
The Accelerator LEAP program supports primary investigators and their teams for 12-18 months with larger-scale funding to move projects along a defined clinical development paradigm with a goal towards transition to a commercial partner following Accelerator support.
Collaboration Through Connections
In practice, the Accelerator is a networked organization forging collaborations both internal and external to Dana-Farber to overcome some of the most significant challenges in cancer today. By leveraging the diverse expertise of the larger innovation community, the Accelerator can support the projects and its mission quickly and efficiently and across a broad spectrum of technologies.
How
We
Work
Team-Based Expertise The Accelerator team is comprised of professionals with extensive experience in medical oncology, therapeutic and diagnostic R&D, business analytics and marketing. Supported by experts both internal and external to Dana-Farber via the Accelerator scientific and business committees, the Accelerator team draws upon the collective knowledge of multiple groups in technology development and commercialization to aid in the mentorship of projects and in management of the portfolio of projects under the Accelerator umbrella. Mary Tolikas Senior Vice President & Chief Innovation Officer PhD Electrical Engineering and Computer Science, MIT MBA Sloan Business School MIT Christiana Iyasere Senior Director, Business Development MD Columbia University College of Physicians and Surgeons, MBA Harvard Business School Harry Rogoff Director, Business Development (Therapeutics) PhD Biology, University of Massachusetts Chan Medical School Luke Dannenberg Director, Business Development (Diagnostics) PhD Biochemistry and Molecular Biology, Indiana University School of Medicine Linda Van Weele Business Development Specialist PhD Cancer, Stem Cells and Developmental Biology, Stanford University and Utrecht University Javi Vinals Camallonga Business Development Data Analyst PhD Biochemistry, University of Oxford Alice McCarthy Editorial Content Manager MBA Babson College Liz Robinson Accelerator Pipeline Marketing Manager BBA in Marketing, University of Massachusetts, Amherst
How to Get Involved INTE R A C T Want to learn more about how to work with the Accelerator? Accelerator support is open to all Dana-Farber faculty engaged in translational science for whom focused mentorship and potential funding could help enable a commercial opportunity. We hold biannual requests for proposals, focused independently on Therapeutics and Diagnostics. Individuals may engage with the Accelerator team at any time; we are always eager and interested to hear how we can help enable the important work of Dana-Farber investigators. Email: dfci_accelerator@dfci.harvard.edu
PAR T N E R Interested in the science behind some of these projects? Accelerator funding is one small step in part of a long pathway toward the creation of successful technologies and impact; our goal is to demonstrate the potential of the science as a solution to elicit follow-on funding for the next stage of development. Please reach out if you are interested in hearing more about the science or want to learn about other opportunities in Dana-Farber’s technology portfolio. Here we have highlighted only a small fraction of the exciting science that is part of the Accelerator and the larger technology landscape of Dana-Farber. Email: dfci_accelerator@dfci.harvard.edu
DO N A T E Looking to support the Accelerator with the potential to change cancer care? Generous philanthropy created and continuous to support the Accelerator and the projects we fund. We are interested in high-risk, high-reward translational science that can change the face of cancer therapy. Please contact our team. Email: Mark_Veligor@dfci.harvard.edu
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