With approximately 1000 agents in clinical development, more than 3000 active clinical trials and over 570.000 patients enrolled, cancer immunotherapies have become a booming success for the global biotech and pharma industry.
Increasingly, new research is showing that agents targeting the immune system can not only be used to fight cancer but also other diseases, including inflammation, infectious diseases, genetic disorders or cardiovascular diseases.
Today, there are 26 different immuno-oncology agents approved for therapy use. Amongst them are immunomodulators that regulate the immune system; cancer vaccines; cell therapies where active cells, such as T-cells are injected into the patient to fight tumor cells; oncolytic viruses that are injected into the patient to target and kill cancer cells; and bispecific antibodies.
The most novel immunotherapy takes a different approach. As a personalized therapy, CAR-T (chimeric antigen receptor) is based on extracting a patient’s own T-cells to modify them to recognize and kill that specific patient’s cancer. Although promising, CAR-T therapies can only be applied to two cancer types so far: acute lymphoblastic leukemia (ALL) and advanced lymphoma.
To date, however, there is still no immunotherapy out there that can target not only a variety of cancers, but also other diseases. We have spoken to Dr. Pierre Charneau, HIV specialist and Head of the TheraVectys and Pasteur Institute Joint-Lab. His discoveries kick-started the use of lentiviral vectors for gene transfer and their medical applications.
Pierre knows all about immunotherapies and has told us about the novel approach that the biotech company TheraVectys is taking in the field of immunotherapies. An approach, by the way, that can not only fight most cancers, but is also showing promising results in fighting major infectious diseases, such as malaria, tuberculosis and HIV.
TheraVectys develops vaccinations based on lentiviral vectors. Pierre, can you explain to us how a vaccine is created with the help of lentiviral vectors?
Lentiviral vectors are gene transfer vectors that are strictly non-infectious and non-replicative. They are already extensively used in both translational and basic research, as well as in gene therapy.
The vaccine is more or less based on the same basic principle of a gene transfer vector, except that instead of encoding for a complementing gene for gene therapy, those vectors encode an antigen, which can be of viral, bacterial, or parasitic origin, or also a cancer antigen. A specific regulation of the expression of the antigen is also included in the vaccine vector.
The main difference with all other vaccine approaches is that those vectors when injected in vivo target dendritic cells, which are the main immune cells responsible for the initiation of a cellular immune response.
The delivery of the antigen to the dendritic cell is done via the so-called endogenous antigen presentation pathway. This means that the proteic antigen is newly synthesized within the dendritic cell and this antigenic protein will be degraded into peptides, loaded onto major histocompatibility complex (MHC) molecules and presented to T-cells by the dendritic cell for its whole life after it has reached maturation.
With this lentiviral technology, antigen presentation is long-standing, which is the key difference with all other vaccine approaches. Other vaccine strategies are usually based on cross-presentation, during which antigen-presenting cells use extracellular protein antigens to induce cytotoxic T-cell stimulation. But antigen presentation, and thus immune stimulation is much shorter lived.
This sustained endogenous antigen presentation pathway is unique to lentiviral vaccines. It induces an intense, diversified and long-term T-cell response, even after a single vaccine injection. Lentiviral vectors are by far the best vectors to induce these intense and long-term T-cell responses.
How do T-cell vaccinations work?
Almost all commercialized vaccines are based on the induction of antibodies – also called neutralizing antibodies – which are generally aimed at blocking infection of target cells by the micro-organism. They therefore protect against the entry of viruses or pathogens into the target cell.
T-cell vaccinations are based on a completely different strategy than neutralizing antibodies. T-cells or cytotoxic T-cells, destroy previously infected cells or even tumor cells through direct contact with the cells and by recognizing small peptides associated to MHC molecules that are present on the surface of infected or tumor cells.
So, unlike neutralizing antibodies, T-cell vaccination is not a vaccine strategy aimed at blocking the entry of pathogens into cells, but rather controls and eliminates the pathology by killing the infected cells or tumour cells.
What is the potential of T-cell vaccinations and what disease areas can they be applied in?
Most commercialized vaccines aim at inducing antibodies. In fact, there’s a lot of disease areas in which there are still no vaccines available, such as AIDS, malaria, tuberculosis and most cancers, despite more than 30 years of research. The common trait of these unmet vaccines is that they require efficient T-cell responses to control the infection or clear the tumor.
The main active immune component that controls these infections or cancers is the cytotoxic T-cell. And before lentiviral vectors there was no technology to elicit an efficient T-cell response.
So the lentiviral platform paves the way for many applications in the T-cell vaccination area, including AIDS, malaria, tuberculosis, but also chronic hepatitis infections, such as the hepatitis B virus and the hepatitis C virus, and last but not least, cancers.
We may start with cancers that are well defined in terms of antigenic profiles, for example, melanomas. But all cancers in principle can be addressed by this therapeutic vaccination. The application field of T-cell vaccinations is quite large and includes major diseases.
TheraVectys is also working on HIV therapies. Pierre, can you tell us more about this?
We are working on an immunotherapy against HIV infection, which is also called therapeutic vaccination. This immunotherapy approach aims at replacing life-long drug treatment of HIV patients with a single therapeutic vaccination. Beyond a therapy, we are also aiming at developing a cure.
In fact, this kind of approach is not new. In a way, nature has shown us what to do: a small proportion of HIV patients, about 1 – 3%, are called long-term non-progressors. This means that although they are not treated with drugs, they never progress to AIDS and show low or even undetectable viral loads in the blood.
The main difference between long-term non-progressors and other HIV patients is the fact that they have a more intense and more effective T-cell response against the virus. So the HIV immunotherapy aims at inducing an immune status in all HIV patients that would be similar to the one observed in long-term non-progressors.
How can TheraVectys’ therapy be compared to CAR-T therapy?
A CAR-T cell is a chimeric, cytotoxic T-cell that is artificially engineered to target membrane proteins found on B-cells, such as CD19 or CD20. The reinfusion of these modified T-cells leads to the complete depletion of B-cells – those cells that secrete antibodies. By doing that it can cure leukemia and lymphoma in some patients.
It has been proven in a large number of clinical trials that CAR-T therapy is effective, but it also has many side effects. This is because contrary to a natural immune response, these artificial CAR-T cells do not have a retro-control, which leads to a complete and irreversible depletion of the B-cell compartment in patients and sometimes initiates the dangerously acute inflammatory reaction known as a cytokine storm.
On the other hand, lentiviral vector vaccines elicit a natural immune response. And contrary to CAR-T cells, which target a single antigen, the lentiviral vaccines target a large number of abnormal motifs on a tumor. This is very effective, because the tumor is attacked from several sides, instead of a single one.
Being a natural response – although induced by the vaccine, but still physiologic – it has all the control mechanisms in place to stop the immune response, when it is no longer needed. So when the tumor is cured, the attack by the immune system stops. A memory response mechanism remains in case of the recurrence of the tumor.
Another big difference is the cost. All approaches based on autologous treatments, so on cells taken from individual patients, are very costly. As opposed to this, the lentiviral vector vaccinations are more cost effective, because they are not personalized.
CAR-T therapy was developed as a consequence of the fact that there was no vaccine technology efficient enough to induce proper T-cell responses. My bet is that lentiviral vector vaccines will replace this costly approach, by naturally stimulating the immune system of patients.
The spectrum of lentiviral vector vaccines is much larger, because it can address infectious as well as oncogenic diseases, whereas CAR-T therapy to date is largely limited to some leukemias and lymphomas.
What are the challenges that come with the development of lentiviral vector vaccines?
Lentiviral vectors, which are universally used in biological research, are still a fairly new vaccine technology. One limitation, because it is new and clinical trials need to be set up in humans, is the question of the integration of vectors into human cells.
In gene therapy, for instance, we use integrative vectors that are aligned with the patient’s genetics and are permanently incorporated into the patient’s chromosomes. When the patient’s cells undergo mitosis, the vector’s DNA is also replicated.
In the vaccine field, however, regulatory agencies, such as the FDA or EMA, largely prefer non-integrative lentiviral vectors for vaccines. But the first generation of non-integrative vectors were less efficient than integrative vectors.
Thus, we recently developed a brand new and efficient non-integrative vector platform. So we now have a new vaccine platform which completely resolves the question of safety due to the integration of these vectors.
Another limiting point of these vectors is their production. Again, these vectors are largely used in gene therapy for rare genetic diseases where you have only a few dozens of patients to be treated. In the field of major infectious diseases, such as HIV, malaria and tuberculosis, we need millions of doses of vaccines. So there is the major question of upscaling the production of these vectors.
We already have programs to manage the upscaling of these vectors. There are several ways to produce them in large quantities and at reasonable prices, compared to the production process of gene therapies, for example. It is still being developed, but it’s an important point to address in order to produce vaccines on a large scale to fight mass diseases.
How do you see the field of immunotherapies developing over the next few years and how would you position TheraVectys within this field?
A few years ago, the field of T-cell immunotherapies was just a concept, because there was no technology to efficiently induce the T-cell response. Today, lentiviral vector vaccines have opened a large field of possibilities. It was the technological breakthrough that was missing to make the concept of immunotherapies truly efficient.
We will soon have the first demonstration of efficacy and safety in humans and a wide avenue will open to a large number of applications. We already have a really impressive protection demonstrations in animal models, including complete protection of Macaques against the Simian immunodeficiency virus (SIV), the monkey equivalent of HIV. We have also found an impressive sterilizing protection against malaria in mice models, as well as a promising protection against tuberculosis.
It is a bit like in the gene therapy field. I was involved in the pre-clinical studies of the very first gene therapy trial with the aim to treat adrenoleukodystrophy, a rare genetic disorder. Being the first gene therapy trial, the discussions with the regulatory agencies were quite heavy and complicated.
But now these vectors are widely used in gene therapy and the interaction with regulatory agencies is much simpler. With the first demonstration of efficacy and safety in humans, I believe there will be a similar development in the field of lentiviral vector vaccines.
As they were the first to apply the lentiviral vector technology to vaccines, Pierre and his team, first at the Pasteur Institute and then at TheraVectys are at the forefront of this promising immunotherapy, which will be the future for a wide range of therapeutic applications. Want to learn more about the company and be a part of its future endeavours? Check out their projects here!
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