A good defense is the best offense. With this premise, cancer research aims to prepare its troops to recognize and eliminate tumor cells without harming the rest of the body. Understanding how the armies of lymphocytes work led to the design of key strategies when chemotherapy or radiotherapy were not enough.
Fifteen years ago, the arrival of immunotherapy marked a turning point. "It is transforming the arsenal," says Luis Álvarez-Vallina, an expert in genetic engineering, whose laboratory modifies and improves the tools used by the immune system against tumors. "Immunotherapy is impacting multiple types of cancers, including solid tumors," highlighting these years of evolution. "I clearly believe that it will transform the future approach to patients. They are achieving very long-lasting responses."
In fact, their latest advances change the concept of cellular therapies, such as CAR-T. "We are in an absolutely transformative era," says the head of the Clinical Research Unit of Cancer Immunotherapy at the 12 de Octubre University Hospital National Center for Oncological Research (CNIO). To get to this point, this immunologist with a research spirit did his residency at the Puerta de Hierro Hospital where he trained with Fernando Díaz de Espada, a reference in Immunology. During his postdoctoral stay in Cambridge, United Kingdom, at the Medical Research Council Centre for Protein Engineering, he worked with Robert E. Hawkins, Stephen J. Russell, and Sir Gregory Winter (2018 Nobel Prize in Chemistry) and designed the first generation of chimeric antigen receptors. A key piece in the configuration of advanced cellular therapies called CAR-T.
What occupies Vallina now is a further step in this type of approach. "We are beginning to understand that the immune system plays a very important role in defense against cancer. Furthermore, we mainly try to understand how we can redirect the function of the immune system to identify and study tumors." But he emphasizes that this is only the beginning, "the tip of the iceberg."
"For now, we only see a part of what it can contribute in cancer; over time, we will also verify its usefulness in other pathological fields. For example, CAR-T cells are starting to be used in autoimmune diseases with spectacular results." Currently, Álvarez-Vallina's team focuses on blood tumors. "In the Immuno-Oncology Unit, we are very focused on developing new advanced cellular therapy strategies, using the patient's own cells for the treatment of blood tumors, hematological neoplasms."
How do they create this 'army' of armed cells?
In the laboratory, they dedicate themselves to creating cells that, in addition to finding and destroying tumors, distribute a kind of molecular daggers that help other cells of the immune system to arm themselves and attack tumors. It is similar to what CAR-T therapies currently do: extract lymphocytes, reprogram them, and return them to the patient. But they provide an extra: the daggers.
"Conceptually, they have a certain similarity," says the researcher to explain the process of STAb cells, their scientific name, which corresponds to the translation of their English acronym: Secreting a bispecific T-cell engager Antibody (STAb). "In both cases, the goal is redirection strategy. We aim to convert any normal lymphocyte from a patient, which, for example, has a predetermined specificity to recognize a pathogen, and arm it to recognize a tumor cell."
The additional power that accompanies this advanced cellular therapy is "the production of a bispecific antibody that allows the establishment of activation bridges not only with the cells that produce it but also with other T lymphocytes that may be in proximity." A distribution of weapons to neighboring comrades, "they ensure that other nearby lymphocytes arm themselves against the tumor and combat it." Therefore, "the therapy has a very remarkable amplification effect." However, effectiveness will not be 100%, "nor will we prevent relapses, but if we combine it with other therapeutic options, we improve the situation of many patients."
Currently, STAb cell therapy is ready to start clinical trials in patients with leukemias and multiple myeloma. "They are very close to being able to be tested in the clinic; we already have funding from the Carlos III Health Institute, through two research trials."
Who would be candidates to try them?
"Those patients who relapse after CAR-T therapy or in whom it did not work. With leukemia and myeloma. Or those who have not had success with any previous treatment." Since there will not be a single patient profile, they will conduct studies called basket, "in which we will include different pathologies and different types of patients," he explains.
"Before measuring effectiveness, with the first trials, we will measure safety. And then, with the requests to the regulatory agency, we will see if we should escalate the dose to find the efficacy data we need." They will not only recruit patients from the Madrid hospital but also from the Clínic Hospital in Barcelona, the Catalan Institute of Oncology in Barcelona, and La Fe in Valencia, initially.
The idea, as Álvarez-Vallina explains, is to include different hospitals "that can provide patients in these conditions." Among the details yet to be finalized is where the dagger cells will be created. "We will try for local production, meaning that production will actually be done here, and then it will be infused into the patients. Or everything will be done in the included hospital centers. It is still to be decided."
The next, still distant step is to make them also work in solid tumors, to make them attack different components of the tumor to prevent them from becoming resistant, or even to combine these therapies with CAR-T cells to treat even the most resistant patients. "This will be more complicated because tumors seek ways to escape the immune system's pressure," acknowledges Álvarez-Vallina. He does not say this lightly because he is convinced "that we will find a way."
His concerns are not only in the laboratory but also in whether his therapies will reach the patients. The issue of access to this type of innovative therapies worries him: "How to address this from a logistical point of view and how to finance these very costly strategies because they are personalized." He confesses that "there is a great challenge from a logistical point of view, more than scientific." Because the researcher is confident that "scientifically it is possible."
"There is a great challenge from a logistical point of view, more than scientific. How to finance these very costly strategies because they are personalized?"
Álvarez-Vallina is also director of the CRIS Immuno-Oncology Unit at the hospital. Therefore, he highlights how this type of public-private collaboration between the CRIS Cancer Foundation and the Madrid center is a unique initiative beneficial for all parties: clinicians, researchers, and patients. "I believe that this type of research units in public hospitals did not exist previously and, really, it is a model that gives us a lot of closeness to the patient," he emphasizes.
Consider that this type of support provides the necessary resources to move forward. "Yes, we have means like those provided by the CRIS Foundation," but the issue of how to finance this type of therapy is recurrent. "It is important to consider that Spain is a country that has a considerable delay in approving therapies that are given the green light by the European Medicines Agency."
The annual report "Indicators of access to innovative therapies in Europe 2023" indicates that in two years, patients have gone from being able to use 53% to 62% of approved drugs in the EU.
The waiting time has increased by more than a month, from 629 to 661 days, almost a two-year delay. Despite the improvements in recent years, "here they are really approved with a lot of delay. And that significantly impacts multiple patients." Alvarez-Vallina highlights the gap between research and clinical trials and the reality of daily practice.
This perspective comes from a laboratory working within a hospital, where science and medical care go hand in hand. Therefore, he insists that these obstacles should be resolved quickly and accurately. The CRIS Foundation helps drive new trials, affirms the researcher.
This collaboration injects 4.36 million euros into the Madrid center. "These types of units exist and have worked in other geographical contexts, such as in Europe and the United States, with great success. It is a very successful model."
This model allows access to resources from other CRIS units, such as the Hematological Tumors unit led by Joaquín Martínez, head of the Hematology and Hemotherapy Service at the Hospital Universitario 12 de Octubre.
"With them, we can coordinate to conduct clinical trials in patients with lymphomas using STAb cells." It also explains how the proximity of the CRIS unit that combines research in immunotherapy in lung cancer and solid tumors, led by Luis Paz-Ares, head of the Medical Oncology Service at the Madrid center, "opens up the opportunity for us to extend this type of therapy to cancers located in organs."