Technology

While autologous CAR-T therapies are increasingly proving to be effective, certain limitations have curtailed its wider use, including lengthy vein-to-vein time, variable manufacturing success and cell potency and high production cost.

In allogeneic CAR T cell therapy, T cells donated from healthy individuals (vs. from patient’s cell in autologous therapy) are engineered to express CAR in a similar manufacturing process and in conjunction, modulated via various approaches to limit immune reactivity against the patient. These therapies are then stored in a bank for off-the-shelf on demand use for patients. This approach significantly improves manufacturing time and success, product reliability, patient access and lowers cost.

However CAR-T cell therapy sourced from healthy allogeneic donors however introduces potential risks with inducing graft‐versus‐host disease (GvHD) in patients. In addition, persistence of infused allogeneic CAR T cells in patients is often limited as a result of recipient immune cell rejection. Thus any approach to allogeneic CAR-T cell therapy strives to tackle these 2 main challenges.

Virus-Specific T Cell’s (VST’s) are highly specialized T cells produced during a viral infection. These cells have the ability to recognize and kill infected cells while activating other parts of the immune system for a coordinated response.

Allogeneic VSTs without any form of genetic modification have been demonstrated to exhibit good safety profile and efficacy in early trials ². Risk of graft versus host disease, graft rejection and other serious reactions associated with current allogeneic cell therapies were low. These qualities of VSTs may enable broad application in the allogeneic setting.

To date, Tessa has successfully manufactured and delivered over 150 VST therapies in a Phase III clinical trial setting.

Preclinical data shows that CD30 targeting potentially helps eliminate alloreactive T-cells and may improve allogeneic cell expansion and persistence. Tessa Therapeutics is thus leveraging on the unique properties of CD30-CAR and VST to establish a proprietary allogeneic cell therapy platform to target a variety of hematological malignancies and solid tumors.  At the core of this platform, Epstein Barr Virus Specific T Cells (EBVSTs) are augmented with CD30-CAR technology to increase the persistence and expansion of VST cells. A therapy using this platform is being evaluated in an ongoing Phase 1 clinical trial in United States. This study is being conducted in partnership with Baylor College of Medicine.

Current CAR-T cell therapies have had limited clinical success in patients with solid tumors. Some of the roadblocks for CAR-T cell therapy in solid tumor targeting includes heterogeneity of cancer antigen expression in solid tumors leading to outgrowth of escape variants, low levels of tumor antigens expressed in organs leading to on-target off-tumor activity, presence of physical barriers restricting immune cell entry, together with the development of an immune suppressive microenvironment. Novel approaches for CAR T cell therapy in solid tumors are therefore urgently warranted.

Tessa’s novel approach to overcome the challenges of applying CAR – cells in solid tumors is to is to combine CAR-T cells and binary oncolytic virus therapy. The administration of this therapy is a two-step process: adenoviruses consisting of oncolytic and helper-dependent adenoviruses are administered locally into the tumor, followed by systemic infusion of tumor antigen targeting-CAR-T cells. The oncolytic virus directly kills tumor cells and while doing so, generates an inflammatory tumor microenvironment that would be more accessible to CAR T cell infiltration. Entry of CAR T cells into these ‘hot’ tumors enables a second wave of tumor killing. The helper-dependent virus encodes for local production of T cell stimulant IL-12 and checkpoint inhibitor anti-PD-L1. This further immunologically primes the tumor and super-charges the CAR T cell for tumor killing.

We are testing this approach in our TT16 Phase 1 clinical trial in United States, where we combine HER2-CAR-T cells and binary oncolytic virus therapy to target HER2-positive solid tumors.This study is being conducted in partnership with Baylor College of Medicine.

CD30 is a transmembrane glycoprotein and is a member of the tumour necrosis factor receptor superfamily. CD30 is expressed on virtually all Reed-Sternberg (RS) cells in Hodgkin’s lymphoma (HL) and can also be found expressed in certain proportion of various Non-Hodgkin’s lymphomas (NHL)^1-10. CD30 expression is stable and consistent even in resistance or relapse following CD30 targeting therapy and retreatment has been established as effective ¹¹. In contrast, CD30 is expressed only on activated T and B cells, which are a small subset of immune cells. This makes targeting of this antigen with little likelihood of major off target-related adverse effect, an extremely promising approach to explore in classical Hodgkin and non-Hodgkin lymphoma.

Chimeric Antigen Receptor (CAR) T cell therapy, or CAR-T cell therapy, is an investigational immunotherapy approach to treat cancer. In autologous CAR-T therapy, white blood cells are collected from a patient’s blood using an automated separation process. The cells are sent to a manufacturing laboratory where they are engineered to produce chimeric antigen receptors on their surface. The engineered T cells are now called CAR-T cells. After testing for the surface expression of CAR, the cells are further expanded in a cocktail of cytokines until the dose level required for treatment is achieved.

Following infusion into the patient’s bloodstream, CAR-T cells recognize and kill the tumor cells that express the targeted antigen on their surface while also continuing to multiply within the patient’s body.

Tessa’s TT11 CD30.CAR-T cells have been shown in preclinical studies that T-lymphocytes engineered to express CARs targeting CD30 are directed to kill CD30-positive HL cell lines ^1-2.

Two independent CD30-CAR-T cell Phase I/II studies conducted by Baylor College of Medicine (Trial Number: NCT02917083), and the University of North Carolina (Trial Number: NCT02690545) for patients with relapsed or refractory CD30-positive Hodgkin lymphoma showed that TT11 CD30-CAR T cells have encouraging efficacy and a favorable toxicity profile in heavily pre-treated patients with Hodgkin’s Lymphoma.^3-4 Results from these trials were recently published in the prestigious Journal of Clinical Oncology in 2020.⁵

Following obtainment of the Regenerative Medicine Advanced Therapy Designation and PRIME designations awarded by the U.S. Food and Drug Administration and European Medicines Agency (EMA), Tessa launched at Phase II pilot study at multiple sites in North America and Europe to investigate TT11 CD30. CAR-T Therapy in patients with relapsed or refractory classical Hodgkin lymphoma. The therapy resulted in favourable outcomes in heavily pre-treated patients. The result were presented in a poster presentation at American Society of Hematology conferences in both 2021 and 2022.

In 2022, Tessa commenced a Phase 1b clinical trial (ACTION) investigating TT11 in combination with Bristol Myers Squib’s nivolumab as a potential second-line treatment for patients with relapsed or refractory CD30-positive classical Hodgkin lymphoma (cHL). Nivolumab is a human IgG4 monoclonal antibody that blocks PD-1. It has been approved by the U.S. Food and Drug Administration (FDA) as a treatment for numerous cancer indications, including classical Hodgkin lymphoma.