iNKT cell therapy Licence from Imperial College London

Overview of the Acquisition

SUDA has secured a Licence Agreement with Imperial College London. The Licence Agreement provides SUDA with the exclusive, global rights to commercialise its invariant Natural Killer T (iNKT) Cell Therapy Platform for the treatment of human disease. SUDA will initially focus on developing products to treat blood cancers.

The work to date with Chimeric Antigen Receptor (CAR)-T cells has ushered in a new era of cancer treatment due to the impressive cure rates that have been achieved using this ground-breaking technology. iNKT cells are a specific subset of immune cells that, once activated, have potent cytotoxicity, rapidly release pro-inflammatory molecules and traffic to tissues. iNKT cells are equipped to undertake cancer cell destruction through their invariant T Cell Receptor (iTCR) that recognises CD1d found on the surface of a number cancer cell types. Once a CAR is introduced into iNKT cells, they have two ways to recognise and kill cancer cells so they are effectively dual targeting. In preclinical studies, this results in increased activity over conventional cell therapies. In addition, iNKT cells are protective against GVHD and will be able to be used “off-the-shelf”, which means they can be produced from a healthy donor, stored frozen and used as required. This alleviates a major challenge for current cell therapies, which is that they must be produced from the patient that will ultimately receive the therapy. This results in delays for patients to access the therapy and increases the costs substantially.

We are very excited to enter into a Licence Agreement with Imperial College London and we look forward to progressing this technology into clinical trials and beyond.

To review the latest CAR-iNKT presentation, click here

What are iNKT cells?

Invariant natural killer T (iNKT) cells are rare but powerful immunoregulatory and effector T cells, playing a pivotal anti-tumour role.  iNKT cells comprise 1–2% of the mouse spleen and less than 0.1% in human peripheral tissues (Berzins SP, et al., Nat Rev Immunol. (2011) 11:131–42). Despite their low abundance, iNKT cells elicit a strong immune response by producing copious amounts of cytokines, which lead to other immune cell responses. Also, they can induce cytotoxicity and therefore play an important role across both innate and adaptive immunity.

What is Chimeric Antigen Receptor (CAR)-iNKT cell therapy?

A CAR-iNKT cell is an iNKT cell that is modified to become “super-charged”, to seek out a specific target on the surface of a cancer cell. iNKT cells can already target cancer cells that have CD1d on their surface but addition of a CAR makes them dual targeting.

The CAR-iNKT cells then have a marker on their surface, a custom designed cell receptor (the CAR). The external recognition portion of this CAR provides new target specificity and after expression in the iNKT cells and following iNKT cell binding to the target molecule found on the cancer cell, the intracellular domains of the CAR initiate iNKT cell activation and tumour killing.

iNKT cells have an invariant iTCR that does not change between individuals and recognises glycolipid (α-GalCer)-bound CD1d, which is found on numerous cancer cells. They are also genetically modified to express a CAR that will attach to a specific target (antigen) on a cancer cell. Once the CAR-iNKT cell binds to cancer cells, they are activated to carry out its destruction.

Dual targeting of CAR-iNKT cells makes them more effective at killing cancer cells than conventional cell therapies

CAR-iNKT cells are dual targeting as they have two ways to recognise, attach to and kill cancer cells – through their invariant T Cell Receptor (iTCR) and CAR. Our lead product has a CAR that targets CD19 on cancer cells. We have been able to show that CAR19-iNKT cells have better activity than their conventional CAR19-T cell counterparts against cancer cells harvested from patients with marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). CAR19-iNKT cells are being developed for the treatment of certain blood cancers.

Rotolo et al., Cancer Cell

Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) cells were isolated from cancer patients and subjected to treatment with CAR19-iNKT cells or CAR19-T cells. CAR19-iNKT cells (red line) outperformed CAR19-T cells (blue line) in terms of cell killing efficacy

When tested using mouse models, CAR19-iNKT cells were able to eradicate tumour cells after 3 days, which is in contrast to other treatments such as CAR19-T cells or animals treated with cells lacking a CAR.

Rotolo et al., Cancer Cell

Tumour cells expressing CD1d were intravenously delivered into mice. Mice were subsequently treated with either: nothing (PBS), unmodified T cells (T) , unmodified iNKT cells (iNKT), CAR19-T cells or CAR19-iNKT cells

In addition, when tested in animal models, CAR19-iNKT cells performed better than CAR19-T cells at prolonging survival.

Rotolo et al., Cancer Cell

Tumour cells expressing CD1d were intravenously delivered into mice that were subsequently treated with normal T cells, normal iNKT cells, CAR19-T cells or CAR19-iNKT cells. Overall and tumour-free survival were measured and CAR19-iNKT (red line) cells outperformed conventional CAR19-T cells (orange line).

CAR19-iNKT cells can enter the brain induce spontaneous secondary remission

Using a model with K562 cells that have CD19 and CD1d on their surface, all animals treated with CAR19-T, brain lymphoma persisted above the threshold of detection in all but one animal. In contrast, the brain lymphoma was eliminated in 13/18 CAR19-iNKT cell-treated animals.

In four animals treated with CAR19-iNKT cells, after initial clearance of systemic and brain lymphoma, relapse developed primarily in the brain at a later stage. In all four mice this relapsed disease eventually regressed without additional treatment, leading to long-term survival.

Rotolo et al., Cancer Cell

Rotolo et al., Cancer Cell

iNKT cells can be used off-the-shelf

The TCR in iNKT cells does not change between humans and iNKT cells have been shown to be protective against graft versus host disease (GVHD). As such, iNKT cells are unlikely to cause safety concerns when produced from a healthy donor and administered to patients.  As the CAR-iNKT cells are intended to be produced from a healthy donor, they will be a more amenable to reaching more patients and at reduced cost compared to current cell therapies.

There are major benefits to having the cell therapy produced “off the shelf”

  • Traditional CAR-T cell therapy manufacturing processes are complicated and expensive: Traditional CAR-T cell therapy requires every patient’s own immune cells to be collected, frozen, genetically modified, expanded to sufficient numbers and frozen again for shipment back to the hospital for patient dosing.
  • ‘Off-the-shelf’ dosing will enable the drug to reach more patients faster: Product produced from a healthy donor that is capable of being stored can be used when required. This will reduce logistical challenges and improve affordability. Patients will not need to wait so they are unlikely to see their condition worsen over the production phase, which may otherwise preclude them from taking the therapy.
  • Starting from healthy donor cells is likely to yield a better product with superior activity against cancer cells: Cells from a patient may have been subjected to cancer cells as well on other anti-cancer therapies that may reduce the quality of the starting material, so they may not be as effective.

CAR-iNKT cells are expected to have a favourable safety profile

CAR-iNKT cells are made up of two components i) iNKT cells and ii) a CAR that is introduced into the cells to recognise, attach to and destroy cancer cells that have a specific marker on their surface. Four CARs targeting CD19 have been approved by the FDA and it is a well-known target. iNKT cells have also been shown to be protective against graft versus host disease and they have been used in more than a dozen clinical trials, including from a patient’s own cells and from a healthy donor, with no major safety issues

iNKT Cells Protect Against Graft Versus Host Disease

Clinical Use of iNKT Cells