New use for foralumab in CAR T-cell therapy
Tiziana has a fully human therapeutic monoclonal antibody, foralumab, currently being developed for nasal, inhaled and oral delivery to treat autoimmune disease and COVID-19; it is the only fully human anti-CD3 monoclonal. Precision Biosciences, Tiziana’s new US partner, is developing “off-the-shelf” (allogeneic) CAR T-cell therapies. CAR T-cell therapy is a powerful new therapy type used for some blood cancers. To make it work, existing T-cells in patients need to be depleted first. This is done using highly toxic chemotherapy agents. The hypothesis being explored is to use foralumab to reduce or replace this chemotherapy in order to achieve a safer treatment regimen and enable more patients to access effective allogeneic CAR T-cell therapy.
Deal with Precision Biosciences, Inc opens possible new use
Precision Biosciences is in the early clinical development phase with three CAR T-cell projects. Foralumab as an addition to the treatment regimen might require at least five years of clinical development and regulatory review as a stand-alone systemic agent given before the CAR T-cell infusion.
The deal has an upfront fee, some milestones and royalties; these are undisclosed. Precision will pay all the development costs.
The application, allogeneic CAR T-cell therapies, is accessible to Precision due to its gene-editing technology. This technology could enable a range of products for different cancers to be available at a lower price than the current high-priced, customised, autologous offerings.
We see this deal as scientifically interesting and, in the long-term, a future potential source of considerable value. Shorter-term, it will have little impact. By passing all costs to Precision, it creates value without distracting Tiziana from its core focus on oral, nasal and lung delivery of foralumab.
Early clinical phase
The area of Chimeric Antibody Receptor (CAR) T-cell therapy is still relatively new. Current products include Yescarta, Kymriah and Abcema. These products are currently made by genetic modification of T-cells taken from individual patients. The manufacturing process takes some weeks and is logistically complex. In addition, as each therapy is custom-made, and not always successful, costs are high and prices are up to $475,000 (plus all the extra costs and hospital time).
To make a CAR T-cell, killer T-cells, a type of white blood cell, have to be isolated. Killer T-cells sense abnormal cells and kill them with one T-cell able to kill up to a thousand cancer cells, they are potent and lethal if triggered. CAR T-cells detect their cancer cell targets through a very complex genetically engineered receptor, the CAR, that is genetically inserted into the cells. Currently, approved products only target some leukaemias and lymphomas and recently multiple myeloma. Many other targets are in clinical development.
The biggest markets will develop if CAR T-cells therapies can be made general, that is allogeneic, so one batch can be used to treat many, different patients. This means they can be cheaper and be stored in the freezer at major cancer centres. All currently approved products are autologous: the therapy is custom manufactured for just one patient using their own cells which is very expensive. The other goal is to develop CAR T-cell therapies against solid tumours. This is proving hard as there are multiple factors affecting the efficacy of T-cells, but globally, clinical development efforts are intensive with many cancer types and targets (cancer antigens) under development.
CAR T-cell
"We see this deal as scientifically interesting and, in the long-term, a future potential source of considerable value."
Precision Biosciences
Precision is a NASDAQ quoted, US company with a market capitalisation of over US$800mln.
Because Precision specialises in genetic modification, it can design a CAR, make the genetic package and insert it into T-cells. The T-cell normally makes a sophisticated receptor (a TCR) that is activated by another receptor, CD3. Precision knocks out the TCR and CD3 genes in the T-cells and inserts genes for a CAR targeting a cancer. The modified CAR T-cells are then grown, a typical dose is billions of cells.
Precision has three allogeniec products in early clinical-stage development with two more approaching clinical development. All of them target blood cancers and known cancer antigens (CD19, CD20 and BCMA).
"Tiziana management believes that an intravenous dose of 2mg will be adequate for a therapeutic response."
Potential use of foralumab in CAR T-cell therapy
Before CAR T-cell therapy can be given, the number of natural killer T-cells in the patient needs to be reduced. This enables the infused CAR T-cells to reproduce rapidly so delivering a much better therapeutic response as they kill the cancer cells.
Targeting CD3 depletes killer T-cells and foralumab is an anti-CD3 monoclonal. It is fully human, the only anti-CD3 having that status. This gives safety advantages and means it is not rejected by the patient’s immune system. The first therapeutic monoclonal was against CD3 so this target is well known. However, targeting CD3 may cause undirected T-cell activation and a cytokine storm so the dose and safety profile need to be clinically determined. Foralumab has already been tested systemically in a phase I study at low doses. Tiziana management believes that an intravenous dose of 2mg will be adequate for a therapeutic response.
Currently, the depletion of existing T-cells is done by combining two toxic agents, called Cy-Flu therapy.
- Fludarabine (Flu) which can cause fevers and brain toxicity
- Cyclophosphamide (Cy) which causes hemorrhagic cystitis, pericarditis, and brain toxicity
They can also trigger secondary cancers. The side effects are serious and can prevent patient attempting CAR T-cell therapy or even kill them.
If foralumab can be used on its own or combined with low dose Cy/Flu, it might reduce overall toxicity and enable more patients to be treated. To gain approval in this indication, foralumab will have to undergo clinical trials and gain an FDA approval. As yet, it is too early to be clear on the potential approved indication.
An analogy is with Tocilizumab, an anti-IL6 monoclonal used to treat side effects of CAR T-cell therapy. This was initially used off label and gained a specific CAR indication later. That was, however, straightforward as the product was already approved for autoimmune disease.
Commercial impact on Tiziana
The deal is exclusive to Precision and restricted to using foralumab with Precison’s allogeneic CAR T-cell therapies. It has an upfront fee, some milestones and a royalty although these are not disclosed. As a preclinical-stage project with high development costs over probably at least five years as a systemic, infused product, we do not expect significant payments soon (although potential royalties could be significant). Development times are likely to be long but are currently not disclosed. If the project shows promise, it might be extended by various routes as it is potentially broadly applicable to other CAR T-cell applications.
Accordingly, we see this deal as scientifically interesting and a potential source of considerable future value. Shorter-term, it will have minimal financial impact. By passing all costs to Precision, the opportunity can be explored without distracting Tiziana from its core focus on oral, nasal and lung delivery of foralumab for autoimmune disease and in the treatment of COVID-19 infection.