Technology

CD30 CAR-T Cell Therapy

CD30 Targeting

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.

References:

1 Gottesman et al. Pathology and Laboratory Medicine International 2016
2 Sabattini et al. Haematologica 2013
3 Kawamoto et al. Hematol Oncol 2018
4 Campuzano-Zuluaga et al. Leuk Lymphoma 2013
5 Gong et al. J Clin Pathol 2018
6 Hao et al. 2 PLoS One 2015

7 Hu et al. Blood 2013
8 Salas et al. Biomarkers 2020
9 Slack et al. Br J Haematol 2014
10 Hoeller et al. Human Path 2010
11 Forero-Torres et al., EHA 2012. Abstract 0213

CAR-T Cell Therapy

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 Cell Therapy

Classical Hodgkin lymphoma (cHL) has a global incidence of about 80,000 and mortality of about 27,000 per year1. Despite major advances in therapy for cHL that have resulted in a improved survival over time2, this disease remains fatal for a subset of patients who either do not respond to initial therapy or relapse despite multiple lines of therapy. Of these patients with refractory disease, only a small subset responds to recently approved targeted therapy or immunotherapy, leaving a significant unmet medical need.

We believe CAR-T cell therapy has the potential to transform cancer care, and therefore are pursuing its development at Tessa. CD30 is expressed on lymphoma cells from patients with both newly diagnosed and relapsed cHL, making it a potentially useful target throughout the natural history of this malignant disease3,4, and thus this was the first disease targeted for Tessa’s TT11 CD30.CAR-T Therapy.

References:

1 Source: Globocan
2 LaCasce et al. UpToDate 2019b
3 Gottesmann et al. Pathology and Laboratory Medicine International 2016
4 van der Weyden et al. Blood Cancer J 2017

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.5

References:

1 Hombach et al. Cancer Res 1998
2 Savoldo et al. Blood 2007
3 Ramos et.al. Blood 2018
4 Grover N.S. et al. ASTCT 2019
5 Ramos et. al. JCO 2020

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 is launching a pivotal Phase II clinical 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 favorable toxicity profile and encouraging antitumor activity of autologous CD30.CAR-T demonstrated in 2 studies also provide strong rationale to expand the study trial to also CD30-positive NHL subtype populations to fulfill important unmet clinical needs 6.7. Tessa has launched a Phase 1 clinical trial at multiple sites in United States to investigate Tessa’s TT11 CD30.CAR-T Therapy in patients with relapsed or refractory CD30 positive Non-Hodgkin lymphoma.

References:

6 Vadakara et al, Chronic Dis Transl Med 2019
7 Grover et al, BMC Cancer 2019

Allogeneic Cell Therapy Platform

Allogeneic CAR-T Cell Therapy

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.

Challenges of Off-the-Shelf CAR T-cells

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.

Tessa’s Allogeneic Cell Therapy Platform

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.

References:

1 Argaet et al., J. Exp. Med. 1994; Campos-Lima et al., J. Exp. Med. 1997; Lim et al., J Immunol. 2000
2 Rooney et al., Lancet. 1995; Heslop et al., Nature Medicine. 1996; Rooney et al., JNCI Monographs. 1998; Haque et al., Lancet. 2002; Haque et al., Blood. 2007; Heslop et al., Blood. 2010; Melenhorst et al., Blood. 2010; Doubrovina et al., Blood. 2012; Prockop et al., ESH. 2018; Barker et al., Blood. 2010; McLaughlin et al., Blood. 2018; Cho et al., Mol Ther. 2015; Chapuis et al., Nat Med. 2019; Tessa’s MABEL trial

Oncolytic Virus Combinations

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 Solid Tumor Targeting Approach

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.

Manufacturing

Building State-of-the-art, GMP manufacturing facility suited for global regulatory standards

Building robust, scalable operational capabilities is a critical aspect of our strategy to rapidly and reliably deliver cell therapies to patients worldwide.

We plan to open our state-of-the-art, 90,000 square foot commercial-scale cell therapy manufacturing facility in 2021. Located in Singapore, it will be one of the leading facilities of its kind in Asia. The facility is designed to support manufacturing for both T cell and CAR-T immunotherapies for our clinical development and future commercialisation needs. Apart from manufacturing, the facility will also have integrated CMC capabilities to enable rapid product development.

The facility is being developed to be in compliance with current Good-Manufacturing-Practice (cGMP) guidelines from the U.S. Food and Drug Administration, European Medicines Agency and other key regulators in Asia.