In this blog series, we showcase top decision makers at pharmaceutical and biotech companies working to advance cancer immunotherapy. They describe their outlook on the opportunities and challenges facing the field, and share where they think the science of immuno-oncology will lead us. Through their generous sponsorship of our research and patient education programs, these companies help to further the mission of the Cancer Research Institute and bring us closer to a future immune to cancer.
In today’s installment, the second in our series, we introduce you to Rafael Amado, M.D., chief medical officer at Adaptimmune. Adaptimmune is a leader in T cell receptor (TCR) cancer immunotherapy with a robust pipeline of cell therapies in clinical trials for patients with solid tumors and blood cancers. The company’s goal is to revolutionize cancer medicine on a global basis by developing TCR therapies with the potential to treat a wide range of cancer types and patients.
Dr. Amado has served as Adaptimmune’s chief medical officer since March 2015 and has over 15 years of experience within the biotech and pharmaceutical industries. He leads Adaptimmune’s clinical development and regulatory strategy and is responsible for the company’s clinical trials across the United States and Europe as part of its strategic collaboration with GSK, as well as the development of Adaptimmune’s pipeline of wholly‑owned research programs. He formerly served as senior vice president and head of oncology R&D at GSK, where he was responsible for integrating oncology R&D activities, from drug target identification to clinical development and registration globally. He joined GSK in 2008 as vice president of clinical development, and served in positions of increasing responsibility. He oversaw the development and registration globally of over 15 novel indications across six products and led the development of a pipeline of products with companion diagnostics in novel areas of cancer biology.
What is your background and how does it support you in your role at Adaptimmune today?
I trained and was board certified in hematology and oncology at the University of California, Los Angeles, where I subsequently remained as a faculty member for over eight years. I knew I wanted to work in oncology since the early days of my medical internship. During that time, the fundamentals of cancer were being delineated in a series of seminal discoveries—a situation that I envisioned would result in exciting therapies years hence. Indeed, oncology has led the medical field in biomedical innovations for decades. This trajectory continues today with the explosion of agents that inhibit or activate pathways in the immune system—the fruit of over a century of research in cancer immunology.
Moved by a desire impact cancer treatment beyond individual patient care, I transitioned to industry over 15 years ago. Prior to joining Adaptimmune in March of 2015, I was senior vice president and head of oncology R&D at GlaxoSmithKline, where I was responsible for integrating R&D activities in the Oncology Therapy Area from initial target identification through clinical development and global registration. During my seven years at GSK, I oversaw the development and global registration of over 15 novel oncology indications across six products. During my career in industry, I have focused on molecular characterization of tumors to maximize benefit to risk, including molecularly targeted treatments co-developed with companion diagnostics, and novel combinations. I have worked in a modality independent fashion, most recently in the adoptive cell therapy field in my current role at Adaptimmune.
What brought you to Adaptimmune, and what did you set out to accomplish there?
I became familiar with Adaptimmune during my tenure at GSK when we evaluated their technology and executed a collaboration with the company in 2014 that included an option to Adaptimmune’s NY-ESO TCR. I was attracted to its deep expertise in T cell biology, protein engineering of T cell receptors (TCR), and to its approach to testing TCR safety to minimize the potential of cross-reactivity following affinity maturation. In 2015, GSK divested its oncology portfolio and I decided to explore opportunities in industry with companies developing innovative immunotherapies. I found Adaptimmune’s approach incredibly compelling, and joined the company as their chief medical officer over three years ago.
Initially I focused on bringing together a group of professionals with extensive expertise in drug development. We now have a world class organization with the shared goal of bringing the first TCR-based adoptive cell therapies to the market. We obtained breakthrough designation for the NY-ESO TCR in synovial sarcoma and recently GSK decided to exercise its option to license the rights to this TCR. Initially, we invested a great deal of time establishing the right collaborations with tertiary care centers as they themselves organized connections within their centers between solid tumor oncologists and hematologists with expertise in cell therapy. We have opened three additional INDs and are actively accruing patients to these programs. The clinical and translational medicine alliance with MD Anderson Cancer Center has been a critical development for us. We have gained access to a wealth of talent from that institution and a large pool of patients are being screened in our clinical trials. We have learned a lot in these past three years, from optimization of conditioning chemotherapy, to the requirements for antigen expression and cell dosing, to the toxicities of these treatments and how to anticipate and manage them effectively. We are putting this knowledge to use as we advance our current proprietary programs in our Phase I and II studies.
What class of immunotherapy does Adaptimmune focus on and why is this approach promising? How is it different from other immunotherapies?
The cornerstone of Adpatimmune’s technology is the enhancement of the affinity and avidity of TCRs and to precisely tune these receptors to recognize targets on cancer cells. This technology makes possible targeting antigens for which the natural affinity of native TCRs is too weak to result in effective T cell immunity.
TCRs, the natural receptors of T lymphocytes, are proteins that recognize antigen fragments bound to HLA molecules which are present in all nucleated cells. Using proprietary technology, Adaptimmune scientists are able to mutate specific regions of the receptor molecule to recognize cancer cells, where the unmodified receptor is inactive owing to the negative selection that self-reactive TCR-bearing T cells undergo in the thymus. This proprietary technology has the potential to be truly disruptive as there is a wealth of targets we can pursue with properly engineered and tested TCRs. Indeed, the dearth of suitable targets is a critical challenge for the development of immune therapies such as adoptive T cell therapies with CARs (chimeric antigen receptors), TCRs, and bispecific constructs. We have compelling evidence of anti-tumor activity in solid tumors to support the proposition that targets uniquely expressed in cancer cells can act as flags to the immune system and trigger T cell killing of cancer cells if the TCR affinity is properly tuned.
While CAR-T cells represent a paradigm shift in the way certain hematologic malignancies are treated, this technology has not succeeded in the treatment of solid tumors. CAR-Ts have antibody fragments on their surface in place of a TCR and can only recognize large extracellular proteins such as CD19 or BCMA, which are present also in normal cells. There are probably not enough targets like these to have an impact across multiple solid tumors. Adaptimmune solely focuses on engineered affinity enhanced T cell receptor (TCR), the potentiation of such TCRs through the use of alternative genes (which we term second generation TCRs), and their application in autologous and non-autologous cell systems. The therapies we investigate are called Specific Peptide Enhanced Affinity Receptor (SPEAR) T cells. TCRs can target any intracellular protein and therefore can be made to be much more specific for the tumor. Moreover, because CAR-Ts have multiple CARs with high affinity in their surface, it may be difficult for T cells to make it into the interior of the tumor mass. TCRs bypass this trafficking hurdle because the frequency of peptide-HLA complexes in tumor cells, and the affinity of the T cells for such complexes are both much lower than those of CAR-T cells. SPEAR technology has already been demonstrated to have antitumor activity in solid tumors and it has the potential to transform the way we think about using cell therapy in cancer care.
In your opinion, what are the three biggest opportunities in immuno-oncology in 2018 and beyond, and why do you think so?
Effectively treating solid tumors is the key challenge for adoptive T cell therapy. Tumors with low mutational burden that lack inflammation are generally resistant to checkpoint inhibitors. Adoptive cell therapy is a promising technology to address these tumors that remain hidden to the immune system. TCR-transduced T cells are a promising strategy, as demonstrated by Adaptimmune’s results in sarcomas using an affinity enhanced TCR against NY-ESO.
Combinations and next generation approaches that overcome inhibitory tumor effects with our SPEAR T cells are also future opportunities. We are studying diligently every patient to better understand what approaches would be most appropriate to circumvent primary and acquired resistance. For instance, we can incorporate additional elements into our SPEAR T cells that can enhance their activity, such as genes that neutralize inhibitory cytokines in the tumor micro-environment that promote T cell expansion, or broaden cellular and humoral immunity through epitope spreading.
The manufacturing of autologous cell therapy remains laborious and there is risk of manufacturing failure in a small proportion of patients. There is a waiting period that can become difficult to bridge in patients with advanced malignancies. The gene transfer methodology is costly as it generally involves replication-incompetent vectors. And the products remain heterogeneous; indeed there is no consensus as to what is the ideal phenotypic makeup of a final product. Given all these considerations, there is a desire in the field to move from bespoke products to “off the shelf” technologies that standardize the material and provide a “just in time” cell material to every patient. We have a collaboration with Universal Cells to develop an “off-the shelf” product for our SPEAR T cells. The final pharmaceutical cell product would consist of T cells differentiated from a stem cell line which, while still HLA restricted, has been engineered to be universally acceptable by any donor, and which contains both our engineered TCRs and possibly other next generation elements.
What’s the single biggest challenge in immuno-oncology today, and how does that apply to the development of your technology?
Access to patients has become a critical factor in the advancement of novel immunotherapies. These products are being studied alone and in combination with standard therapies and other novel immunotherapies in multiple indications, lines of therapies, and across thousands of trials. Our studies compete with treatments that are easier to administer, some of which have a record of established activity. In addition, cell therapy studies using TCRs require that patients express the right HLA type and that their tumors express the right antigen. Therefore adoptive cell therapies have additional complexities that make trials difficult to execute. As with any first-in-human oncology program, we have the challenge of treating very ill and heavily pretreated patients. As our therapies evolve and we move toward marketing authorization, we anticipate that we will move up the lines of therapy and reach a larger pool of patients who could potentially benefit from these treatments. The current challenges of access to patients and the inefficiencies of the clinical development process involving multiple large controled studies calls for paradigm changes in the way novel therapies are studied.
An additional key challenge for cell therapy and for cancer immunotherapy at large is the identification of predictors of activity, circumventing resistance, and increasing the depth and durability of responses. One can envision that discoveries relating to mechanisms of resistance in cell therapy will lead to new generations of engineered cells containing genetic elements that modify the behavior of the effector T cells, other inflammatory cells, or the tumor microenvironment to maximize efficacy and decrease toxicity.
What role do you envision nonprofits like the Cancer Research Institute playing in accelerating the field of immuno-oncology?
Relationships with nonprofits are critical. CRI has a stellar track record of fostering collaborations and executing innovative studies. Your organization can increase awareness of specific trials, can broker partnerships with other companies to facilitate rational combinations, and can bring together companies and academic institutions to design and execute innovative trials that perhaps individual companies are unable to conduct due to limitations in resources and a need for focus. As I alluded to above, facilitating access to patients is a critical need in the field, and CRI can facilitate clinical experimentation by promoting collaborations and directly executing trials with elite centers. Fostering a broad understanding of TCR technology and the role of T cells in the immune system is critical to Adaptimmune’s success. We see the Cancer Research Institute’s reach and ability to educate and distill these concepts to the medical and the patient communities as fundamental to the success of any potentially disruptive immunotherapy.
Interested in learning more about T cell receptor therapy? Watch our webinar with TCR expert Philip D. Greenberg, M.D., head of the immunology program at the Fred Hutchinson Cancer Research Center, professor of medicine and immunotherapy at the University of Washington, and a member of the CRI Scientific Advisory Council.
Banner photo by Joel Filipe on Unsplash.