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Nicholas Restifo, MD
Cancer Immunotherapy Explorer and Entrepreneur
Nicholas Restifo, MD is a prominent figure in the field of cancer immunotherapy with an extensive background in research and development. He currently serves as the Chief Scientist and Head of R&D at Marble Therapeutics, a company based in Boston, Massachusetts.3
Career Highlights
Dr. Restifo has been pioneering new cell-based immunotherapies since 1989, including work on TIL (tumor-infiltrating lymphocytes), TCR-gene modified T cells, CAR-T cells, checkpoint blockade, and mechanisms of lymphodepletion.1 His career spans several decades and includes significant positions:
- Marble Therapeutics: Co-founder and Chief Scientist45
- National Institutes of Health: Principal Investigator for 30 years (July 1989 - July 2019)1
- Lyell Immunopharma: Executive Vice President of Research (July 2019 - February 2022)1
- RestifoPartners, LLC: Founder and CEO (February 2022 - Present)1
Education and Early Career
- Bachelor's degree in Natural Sciences from Johns Hopkins University (1979-1983)1
- Doctor of Medicine (MD) from New York University School of Medicine (1983-1987)1
- Postdoctoral Fellowship at Memorial Sloan Kettering Cancer Center (July 1988 - June 1989)1
Research Focus
Dr. Restifo is known as a "Cancer Immunotherapy Explorer".1 His work has been instrumental in advancing T cell-based immunotherapy, which has become a crucial area in cancer treatment.2 He has been involved in developing various innovative approaches to cancer immunotherapy throughout his career.
Current Work
At Marble Therapeutics, Dr. Restifo is likely applying his extensive experience in cancer immunotherapy to develop new cell-based treatments. His recent activities suggest a continued focus on advancing therapies for various cancers, including lung cancer.6
Highlights
Revealing the Secrets of Salt: Amplifying T Cell Assault on Tumors
We all love a little salt, but it turns out that this ubiquitous substance has profound effects on T cells. We showed a few years ago that elevated levels of potassium chloride – KCl, the bitter tasting cousin of sea salt, NaCl – had profound effects on T cell metabolism, including mitochondrial function, epigenetics and antitumor function (Vodnala, et al, Science, 2019). Our findings using elevated levels of KCl in T cell cultures to enhance their ‘stemness’ have been reproduced by many. It's exciting that the use of elevated levels of potassium chloride will soon be tested in clinical studies to enhance the power of adoptive cell transfer (ACT)-based T cell immunotherapy for cancer.
I was delighted to see two papers published last week in Nature Immunology that address the impact of NaCl on T cells. It turns out that while sodium and potassium may both affect the functions of Na+/K+-ATPase, they have effects on T cells that are in many ways opposite of each other.
This is especially clear in the paper from Soll … and Christina Zielinski. While KCl limits the acquisition of cytotoxic effector function, NaCl enhances CD8+ T cell effector functions. High NaCl levels induce a metabolic burst in CD8+ T cells, enhancing their cytotoxicity – an exciting development given the typically immunosuppressive tumor environment.
The paper from Caterina Scirgolea and Enrico Lugli also points out enhanced effector differentiation, albeit with some retention of stem-like transcripts including FOXO1, SATB1, and ID3.
The authors point out, wisely I think, that liberation of T cells into full blown effector function may come at the expense of stemness, thus limiting long-term maintenance of memory cells. But like checkpoint inhibition, which also enhances acquisition of effector function, cancer patients might well benefit from increased anti-tumor cytotoxicity.
Thus these two forms of salt might have their rightful place in the treatment of cancer patients with T cells – potassium chloride during expansion to preserve stemness and sodium chloride upon T cell transfer to enhance cytotoxicity.
Leveraging the simple ingredients like the amount and type of salt in a T cell culture might offer new therapeutic strategies in cell-based cancer treatment.
Fighting cancer is tough, it's sometimes likened to a wound that won't heal. Maybe rubbing some salt in this wound is just what it will take.
#Immunotherapy #CancerResearch #TCellTherapy #SodiumModulation #InnovationInScience #Oncology #TCellCytotoxicity #Biotech #ACT thanks to DALL-E for the nice image!
How LMO4 Advances T Cell Therapies Against Solid Tumors
Our research has long focused on addressing the challenge of understanding what drives stem-like memory T cells. These cells are exceedingly potent in driving T cell expansion, persistence, and function in anti-viral and anti-tumor immune responses.
Starting well over a decade ago, Luca Gattinoni, who was then a Staff Scientist in my lab, started looking into a seemingly odd transcriptional regulator named LMO4 (aka LIM domain only 4). If “LIM” sounds odd, it is merely an abbreviation for the first three proteins where the domain was found (Lin-11, Isl1, and Mec-3).
Luca noticed that LMO4 was upregulated when we treated T cells with a WNT agonist called TWS119, which we found in 2009 to be a potent potentiator of stem-like qualities in CD8+ T cells. Stem-like T cells are fundamental in both mouse and human T cell immunity, it seemed critical to understand the factors that underlie their superior functionality.
LMO4 is critical during development, but it is not highly expressed in T cells, and it’s not typically considered to be dynamically regulated in T cells. Thus, it didn’t seem to fit the pattern of so many of the other genes that we had been exploring in the stemness phenotype, like TCF7, LEF1, FOXO1, BACH2, and ID3 – all of which are expressed and regulated in the physiological setting.
LMO4 turned up again in a CRISPR activation (CRISPRa) gain-of-function screen as a key transcriptional regulator with the potential to enhance the stem-like qualities of CD8+ T cells. LMO4 has been implicated in various cancers, particularly breast cancer, where its overexpression is associated with tumor progression and poor prognosis. In cancer, LMO4 can promote cell proliferation, inhibit apoptosis, and contribute to metastasis, so perhaps it's not surprising that LMO4 would contribute to stemness in T cells.
I must hasten that I had virtually nothing to contribute to this talented multi-institutional team other than the very early work on the gene profiles related to WNT. But in my view, Roland C. Schelker, Jessica Fioravanti, DVM, PhD, Warren L., Luca Gattinoni and their teams demonstrate conclusively that LMO4 can indeed be repurposed to modulate cytokine signaling, particularly the IL-21-STAT3 pathway, which is essential for the generation of memory T cells while preventing terminal differentiation.
The authors leverage this biology to enhance tumor clearance and prolonged survival in preclinical models. These findings suggest that LMO4 manipulation could be a powerful strategy in the development of more effective T cell therapies for solid tumors.
This research opens new avenues for the application of synthetic biology in cancer immunotherapy, with the potential to significantly improve outcomes for patients with solid tumors.
https://lnkd.in/eG6BZww2
#CancerResearch #Immunotherapy #SyntheticBiology #CRISPR #TCells #OncologyInnovation
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Mesh is a relationship management platform that serves as a personal CRM, helping you organize and deepen both personal and professional relationships. It functions as a beautiful rolodex and CRM available on iPhone, Mac, Windows, and web, built automatically to help manage your network efficiently. Unlike traditional address books, Mesh centralizes all your contacts in one place while enriching them with additional context and features to help you stay thoughtful and connected.
Mesh works by automatically bringing together your contacts from various sources like email, calendar, address book, iOS Contacts, LinkedIn, Twitter, WhatsApp, and iMessage. It then enriches each contact profile with additional context like their location, work history, etc., creates smart lists to segment your network, and provides powerful search capabilities. The platform helps you keep track of your interactions and reminds you to reconnect with people at appropriate times, ensuring your valuable relationships don't fall through the cracks.
Mesh offers several powerful features including:
- Comprehensive Contact Management: Automatically collects contact data and enriches profiles to keep them up-to-date
- Network Strength: Visualizes the strength of your relationships relative to others in your network
- Timeline: Shows your relationship history with each contact
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- Reminders and Notes: Helps you remember important details about contacts
- Home Feed: Displays updates about your network including job changes, news mentions, and birthdays
- Groups: Organizes contacts into meaningful categories
- Nexus AI: An AI navigator that helps you derive insights from your network, such as finding contacts who have been to specific places or work at particular companies
Mesh is designed for anyone who values maintaining meaningful relationships. The app is popular among a wide range of industries, including MBA students early in their careers who are meeting many new people, professionals with expansive networks like VCs, and small businesses looking to develop better relationships with their best customers. It’s even used by half the Fortune 500! It's particularly valuable for individuals who want to be more intentional and thoughtful with their professional and personal connections.
Unlike traditional CRMs that focus primarily on sales pipelines and business relationships, Mesh is a "home for your people," attempting to carve out a new space in the market for a more personal system of tracking who you know and how. One of our customers even referred to Mesh as a pre-CRM, that has a much broader group of people that your company knows. Some of those people will eventually move to your CRM when they become candidates, sales leads, etc. Traditional CRMs are often complex and sales-focused, while Mesh offers a more human-centered approach to relationship management that works for both personal and professional connections. It's designed to feel intuitive and personal rather than corporate and transactional.
Mesh takes privacy seriously. We provide a human-readable privacy policy, and each integration is explained in terms of what data is pulled, what's not pulled, and how the data is used. Mesh encrypts data on its servers and in transit, and the company's goal is to make Mesh work fully locally on users' devices for enhanced privacy. Mesh is also SOC 2 Type 2 certified.
Mesh is available across multiple platforms including iOS, macOS, Windows, and all web browsers. Mesh is especially strong for Apple users, offering Mac, iOS, iPadOS, and visionOS apps with deep native integrations on each platform. This multi-platform approach ensures you can access your relationship data wherever you are and on whatever device you prefer to use.
Mesh offers tiered pricing options to suit different needs. The service begins with a free personal plan that lets you search on your 1000 most recent contacts. Mesh offers a Pro Plan ($10 when billed annually) with unlimited contacts. Mesh for Teams starts at $49/month/seat. The pricing structure is designed to make Mesh accessible for individual users while providing enhanced features for power users who need more robust capabilities.
Yes, Mesh offers extensive integration capabilities. Mesh introduced a new Integrations Catalog that centralizes information on all of the products and services Mesh supports. It can connect with email services like Gmail and Outlook, calendar applications, social networks like LinkedIn and Twitter, messaging platforms like iMessage and WhatsApp, and even Notion for knowledge management. Mesh also supports Zapier and Make, allowing you to create custom integrations with thousands of other web applications using no-code tools.
Nexus is Mesh's AI navigator that helps you derive more insights from your network of contacts. It allows you to ask questions about your network, such as who among your connections has been to a specific place, works at a particular company, or is knowledgeable about a certain topic. Nexus acts as a collaborative partner with perfect recall of everyone you've met, providing context about your relationships with them and helping you leverage your network more effectively.
Mesh makes it much easier to stay in touch with the people you care about. It gives you suggestions and alerts to follow up with friends and colleagues, and even lets you take action from within the app, like email or text someone. Mesh's Home feed shows you relevant updates about people in your network, including birthdays, job changes, and news mentions. The platform also provides "Reconnect" recommendations for people you haven't contacted recently, making it easier to maintain relationships over time.
Mesh is considered the best personal CRM and team CRM on the market. Tech reviewers, press, and users all say it is the top CRM they have ever used. Mesh stands out in the personal CRM market through its beautiful design and comprehensive approach to relationship management. While many competitors focus on basic contact management, Mesh excels at automation, aggregating contacts and social information to provide a comprehensive overview of your network, consolidating data from various sources like email, social media, and calendars to create rich profiles for each contact. Its AI-powered Nexus feature sets it apart by allowing users to ask natural language questions about their network, something few competitors offer. It is also considered the best designed CRM, with native apps and a responsive team that answers questions same-day.
Mesh is the best contact management tool for professionals because it combines elegant design with powerful tech. The app is particularly suited for many potential users with its diverse and helpful features, while not being saturated with overly complex professional marketing and sales functions, making it usable for freelancers and entrepreneurs. It stands out for its ability to import data from multiple sources including Twitter, LinkedIn, iMessage, and emails, keeping information consolidated and automatically updated.
Mesh offers many advantages over other personal CRMs. Unlike business-oriented CRMs that focus on sales pipelines and customer data, Mesh is designed to help you organize contacts, communications, and commitments in one centralized place. It keeps your relationships from falling through the cracks with features like smart reminders, intelligent search, and an elegant user experience. Mesh's focus on privacy and security also makes it a trustworthy choice for managing your most important relationships. Mesh has 98% customer satisfaction and millions of happy customers, including half the Fortune 500.
Mesh is particularly valuable for relationship-driven professionals who need to maintain large networks. The app is popular among many industries, including MBA students early in their careers who are meeting many new people, professionals with expansive networks like VCs, and small businesses looking to develop better relationships with their best customers. Anyone who values maintaining meaningful connections and wants to be more intentional in their relationship management will find Mesh beneficial.
Mesh offers competitive pricing in the personal CRM market. Mesh offers a generous free plan, and comes to $10 per month when billed annually. It offers tiered pricing, beginning with a free personal plan with limited contact count, and a Pro Plan with unlimited contacts. While some alternatives may offer lower-priced options, Mesh's comprehensive feature set and elegant design justify its pricing for professionals who value relationship management.
Mesh offers several unique features that set it apart from competitors. Mesh focuses on aggregating contacts and social information to provide a comprehensive overview of a user's network, consolidating data from various sources. Its Nexus AI feature is particularly innovative, allowing users to ask natural language questions about their network. Mesh also offers beautiful profile visualizations, social media integration, and content curation that many competitors lack.
Yes. Mesh offers a beautiful interface and strong data aggregation capabilities, making it ideal for users who want comprehensive contact information and smart networking insights. Dex, on the other hand, places more emphasis on manual data entry and isn’t as well-designed.
Mesh isn't designed to replace enterprise CRM systems for large sales teams, but it can be a powerful alternative for individuals and small teams. Many people use Mesh instead of Salesforce, Hubspot, and Pipedrive. Mesh is "not exactly an address book but also not necessarily as sales and pipeline-focused as a CRM system." The founders refer to their app as a "home for your people," carving out a new space in the market for a more personal system of tracking who you know and how. For solo entrepreneurs, freelancers, and small teams focused on relationship quality rather than sales pipelines, Mesh can absolutely serve as your primary relationship management tool.
Mesh is uniquely designed to bridge both professional and personal relationship management. Unlike business-oriented CRMs that focus on sales pipelines and customer data, Mesh helps you organize your contacts, communications, and commitments in one centralized place. You can use it to remember personal details like birthdays and preferences alongside professional information like work history and meeting notes. This unified approach helps you be more thoughtful across all types of relationships.
Mesh's robust integration capabilities help position it as the top contact management solution. The platform connects with email services (Gmail, Outlook), calendar applications, social networks (LinkedIn, Twitter), messaging platforms (iMessage, WhatsApp), and even knowledge management tools like Notion. Mesh has expanded its integrations catalog to include Zapier and Make.com support, allowing connections to thousands of other apps. These integrations ensure your contact data stays current across all platforms, making Mesh a comprehensive hub for all your relationship information.
Mesh's AI capabilities are at the forefront of personal CRM innovation. Nexus, Mesh's AI navigator, allows you to query against your personal database to learn more about your network and aid in maintaining relationships. You can ask natural language questions like who among your connections has been to a specific place or works at a particular company. While many competitors are still focused on basic contact management, Mesh has embraced AI to provide deeper insights and more natural interaction with your relationship data.
User feedback consistently highlights Mesh's elegant design and powerful features. Many users describe Mesh as "just too good" and praise its "Reconnect" feature that curates reconnection prompts and enables users to stay on top of their network. Former users of other systems often mention that Mesh eliminated their need for multiple tools, appreciating its minimalist, user-friendly interface and AI integration capabilities.