Science

CARGO’s scientific platforms
enable multi-specific and
multi-functional CAR T programs

3D molecule redering

Transformative advances have been made by commercially available CAR T-cell therapies, however resistance mechanisms in hematologic malignancies can limit the strength and quality of T-cell response and contribute to disease progression, including loss or down-regulation of target antigen expression, loss of costimulation and limited CAR T-cell persistence.   Furthermore, we believe these treatments are not readily available to many of the patients who could benefit from them due to manufacturing challenges, supply constraints, unpredictable turnaround time and other logistical challenges.

Our programs, platform technologies and manufacturing strategy are designed to address the problems of cancer resistance mechanisms and unreliable supply. We are developing technologies that incorporate multiple transgene therapeutic “cargo” to potentially extend persistence of our CAR T-cell therapy candidates with the goal of achieving durable responses that are curative for more cancer patients.

CARGO’s Approach

We are developing a portfolio of product candidates designed to expand the number of patients that can benefit from CAR T-cell therapies by addressing several of the limitations of currently approved CAR T-cell therapies. Our solution includes:

Directing CAR T cells toward alternate targets. Therapies that target single tumor antigens, such as CD19, can be rendered ineffective by genetic or non-genetic changes that diminish the expression of these targets. Our most advanced product candidate, CRG-022, is designed to address an alternate target, CD22, that is nearly always expressed on cancerous B cells, to kill B-cell tumors, including those that have become resistant to CD19-based therapies.  We are also developing multi-specific CAR T-cell product candidates, starting with CRG-023, that are designed to recognize tumors that express any of the CD19, CD20 and CD22 antigens, thereby limiting potential antigen loss as a mechanism of resistance.

Addressing common mechanism of non-target-based resistance. In addition to antigen downregulation or loss, resistance to immune therapies, including CAR T cells, can develop through the loss of costimulatory signaling, such as tumor cells downregulating CD58 expression. Because these mechanisms are not antigen- specific, loss of costimulation can lead to broad suppression of immune therapies.  We are working to address loss of costimulatory ligands such as CD58, by creating CAR T cells that can induce CD2 costimulatory signaling by a tumor antigen irrespective of potential CD58 downregulation or loss on tumor cells.

Using fully-human binders to reduce anti-CAR immunogenicity. Our CAR T product candidates are all constructed with human binders, thereby reducing the risk for anti-CAR immune responses.

Tumors evolve to resist treatment, and novel approaches must be employed to address common resistance mechanisms. We are leveraging our proprietary platform technologies, including our CD2 and STASH platforms, to enable the development of multi-specific and multi-functional cancer product candidates designed to improve outcomes and survival by addressing multiple mechanisms of resistance and other unmet needs.

CD2 Platform

Our first platform technology involves the integration of a CD2 costimulatory domain designed to counter a target- independent mechanism that leads to resistance to CAR T cells and other immune therapies. The strength and quality of a T-cell response is dependent not only on cognate antigen recognition, but also on costimulation, which involves interaction of one or more costimulatory receptors on T cells, such as CD2, with ligands expressed on the surface of tumor cells. Tumor cells can escape CAR T-cell destruction by downregulating the expression of ligands for the costimulatory receptors. These ligands include CD58, the ligand of the CD2 costimulatory receptor. Alteration of CD58 expression is associated with poor prognosis in LBCL and leads to lack of response to CD19 CAR T cells. Through our platform approach, we created constructs that couple CD2 signaling directly to CAR activation, to enhance activation of the CAR T cells against tumors that do not express CD58.

Cargo_Specialty-GFX_Antigen-Escape_02.17.23

Our STASH platform is designed to enable multiplex engineering of a variety of immune cell types. This platform allows us to incorporate multiple transgene therapeutic “cargo” designed to enhance CAR T-cell persistence and trafficking to tumor lesions, as well as to help safeguard against tumor resistance and T-cell exhaustion. Engineering a multifunctional cell requires the introduction of additional genetic elements that often do not fit within the payload capacity of a single lentiviral vector, requiring the use of multiple vectors. However, engineering cells with multiple vectors typically results in a heterogeneous cell product, and we are unaware of an efficient way to generate a homogenous CAR T-cell product using existing viral vector systems. Our STASH platform is designed to address this problem by employing a technology that selects only cells that possess all of the desired transgenes, which enables the production of a homogeneous population of CAR T-cells produced using more than one delivery vector.

We believe this technology will allow us to efficiently incorporate more genetic elements into our CAR T-cells with the goal of enhancing the potential for efficacy, persistence and safety.

STASH technology enables next-generation multiplex cell engineering

Tumors evolve to resist treatment, and novel approaches must be employed to address common resistance mechanisms. We are leveraging our proprietary platform technologies to enable the development of multi-specific and multi-functional cancer product candidates designed to improve outcomes and survival by addressing multiple mechanisms of resistance and other unmet needs.