Highlights from a live keynote by Bahija Jallal, Chief Executive Officer at Immunocore
Bahija Jallal, Chief Executive Officer at Immunocore delivered a fascinating keynote on TCR therapies. Candace Kastanis sums up the session.
Dr. Jallal opened with the fact many immersed in the scientific community believe T cell engagers represent an exciting new modality.
T-cell engagers show many possibilities for a new design of various treatment applications towards hard to treat infections and diseases.
The adaptive immune system has two distinct components.
One is humoral immunity, and the other is cellular immunity whereas, the B cells can develop into monoclonal antibodies.
She notes that collectively as a field, the scientific community is pleased with the development of antibody-driven therapeutics.
However, now they are turning their focus towards the second arm of the immune system, the adaptive immune system.
Protein engineering is the heart of the therapeutic landscape and continues to inspire novel drug discoveries.
Monoclonal antibodies offer a vast range of possibilities towards clinical advancements.
However, despite the measureable success in this area of research, most antibody driven therapeutics only target about 10% of the cell surface proteins or soluble proteins.
This concept represents the foundation for the T cell therapeutic research effort led by Dr. Jallal’s research team.
The team set a goal to find viable therapeutic strategies for the remaining 90% of the proteium.
Dr. Jallal’s team overcame several challenges associated with the development of T-cell therapeutics.
First, the T cell receptors that are membrane-bound have to become both stable and soluble. Additionally, the T cell receptor displayed low affinity.
Therefore, the Immunocore team increased the affinity by a million times. They discovered that by the increasing affinity, they also had to increase the specificity.
The team also had to modify the molecular structure of the T cell in order to activate the effector function. The idea was to redirect T cells so they can target and lyse tumor or affected cells.
This described mechanism of action represents the platform for the T-cell adapative technology developed by the Immunocore Team.
The team noted that, because you can modify the effector system, or downregulate the immune system, it provides an avenue for additional applications.
This is evident in the case of cancer or infection; the idea is to activate the immune system via modifications applied to the T-cell signaling pathways.
In the case of autoimmune disorders, this same concept is applied by to down-modulating the immune system using several effectors such as PD1 (programmed cell death protein).
This in turn makes it possible for using these applications referencing a specific organ with a goal to eliminate the use of steroids as a treatment option.
Pioneering further into this concept meant producing viable solutions for some questions we just did not have answers to prior to the experimentation and research processes.
Some of the more questionable challenges were:
How to turn a molecule into drug candidates and then into the medicine?
How to find a peptide? The team realized they did not have an algorithm to predict a peptide which will make it to the cell surface.
IMMspect. Target Identification Platform Highly sensitive mass spectrometer identity peptide bound HLA
The Immunocore teams entered into a process that involved characterizing and quantifying the peptides into referenced libraries. To date, over 700,000 validated peptides are cataloged.
Additionally, a Dual TCR Platform which consisted of a library with two subunits was created. The two tools used for T cell cloning are TCR and Peptide methodology.
Preclinical ToX Platform
The audience was presented with a video of T- cell redirection illustrating its high specificity.
There is much excitement surrounding the developments in immunotherapy, but we are only still actively treating only 40% of the patients.
Only TCR therapeutics are able to treat intra cellular proteins like gp100. The Immunocore research team tested the TCR based therapeutics on Melanoma: Cuteaneous vs. Uveal.
The properties of each were notated for comparison against other tumor related cancers:
Cutaneous
Uveal
Data suggests that IMMtac MOA is distinct from PD1 checkpoints. This data led Dr. Jallal’s team to perform in 3 separate Melanoma based clinical trials.
Dr. Jallal emphasized the results of the trial using TEBE which is now in a Phase 3- trial which offered results pivotal to our research and drug approval.
The clinical design was a randomized trial with 370 enrolled patients with Uveal Melanoma.
They left the choice of antiviral selection to the investigators. 82% of the investigators chose Embrel.
The biomarkers consistent with proposed mechanism of action involving Cytokine induction and T cell trafficking.
The mechanism is working as it supposed to. The adverse events all consistent with TEBE MOA and were manageable and predictable.
Most of the adverse effects were consistent with this type of drug therapy, with the most common being a rash.
The dropout rate was only 2% vs. the Investigator’s choice at 4%.
They finished the randomizing the trial in June and the primary endpoint were found to be o/s statistically significant.
Therefore, Immunocore was granted breakthrough designation by FDA. Robust survival was entered as .51 making it the best rate in immunotherapy.
Dr. Jallal spoke enthusiastically about the status of their ongoing clinical studies.
She indicated, “Immunocore’s goal is to explore the monotherapy activity, cancer combination and adjunctive therapeutic functionality.
As such, Immunocore entered this space with three major projects:
Patients must be on anti-viral. Hep B Is a DNA-based virus so it is imperative to have a viral integration to take part in the clinical trial.
The infected cell in the liver makes a reservoir that consistently produces viral proteins. Exhaust immune suppression. Most of the patients on anti-viral for the rest of their lives.
The goal of these experiments is to eliminate the reservoir and target non-exhausted T-cells in order to eradicate the virus. This direction is aimed towards a functional cure vs. a standardized treatment.
Researchers decided to take a page from the cancer trials and began by characterizing all peptides thus creating a funnel of selection from the peptides presented.
We were able to select one for introduction into the clinical space.”
IMC-1109V (Envelope Specific 1mm TAV) Data was published
Immunocore dosed first patient in June and the schematics of this clinical design testing are well controlled.
Primarily, we are addressing safety and other biomarkers. Immunocore is beyond excited about this program and is already looking towards the future.
A follow-up program is on HIV+ patients, however, they should be on antivirals. As referenced above, the goal is to get rid of the reservoir.
Dr. Jallal said, “Immunocore is the most advanced TCR bispecific company and is actively targeting three areas with 5 clinical stage programs as mentioned above.
The company mission is to pioneer a paradigm shift in Immune Oncology.”
