CAR T-cell therapies have achieved transformative clinical benefit in the treatment of liquid tumors. Unfortunately, resistance to treatment limits their effectiveness and durability in up to 60% of patients. In addition, access to these life-changing therapies continues to be a challenge for many patients. CARGO’s unique scientific approach applies its innovative engineering and manufacturing technology to create potentially best-in-class CAR Ts that enable multi-modifications and more “cargo” with a focus on overcoming cancer resistance mechanisms. In order to drive better outcomes and experiences for patients with liquid tumors and successfully treat solid tumors, next-generation CAR T-cell therapies need to retain their cancer killing ability by integrating enhancements that maintain T-cell activity longer in the face of the complex tumor microenvironment.
Our proprietary platform technologies enable us to engineer and develop next-generation best-in-class CAR T-cells that incorporate complex therapeutic “cargo” with the potential to achieve durable responses that are curative for more cancer patients. Leveraging our technology, we are able to integrate multiple complex functions and bespoke engineering components that we believe are necessary to overcome various mechanisms of tumor resistance, to counter inhibition in both liquid and solid tumors, and, in the allogeneic setting, to evade immune rejection.
Sixty percent of large B-cell lymphoma (LBCL) patients treated with CD19 CAR T-cell therapies do not experience durable responses due to resistance, and many patients lack access to these potentially curative therapies. For patients with LBCL that relapse or are refractory (R/R) to CD19 CAR T therapies, outcomes are poor. CARGO’s lead program targets CD22 (an alternate antigen that is expressed on most B-cell lymphomas) for patients who relapse after CD19 CAR T-cell therapies, including those with CD19 loss or downregulation.
Antigen escape is a common mechanism of resistance to first generation CAR T therapy. Tumors that lose or reduce expression of the targeted antigen evade the activity of CAR T therapy. CARGO engineers CAR T-cells that target more than one antigen on cancer cells, preventing escape through loss of any single targeted antigen and thereby enhancing the potency, persistence and durability of the CAR T therapy.
CD58 is an antigen expressed on lymphoma cells that plays an important role in immune system recognition and response. In LBCL, CD19 CAR T-cell therapies require expression of functional CD58 on lymphoma cells, however, 25% of patients with CAR eligible LBCL present with mutated or absent CD58. CD58 loss has also been observed in other tumor types (myeloma, AML, colon cancer, melanoma).
CD2 is a costimulatory receptor expressed on T and NK cells that naturally binds to CD58. CARGO is leveraging its CD2 platform to create novel CAR T-cell therapies that employ the CD2/CD58 co-stimulatory pathway to increase T-cell persistence and sustained anti-tumor activity, and ultimately enhance efficacy and outcomes for patients.
Treatments that incorporate methods and tools to enhance T-cell persistence may achieve better and more durable responses to therapy. CARGO uses fully human CAR components in its CAR T-cell therapies to decrease the risk of immunogenicity, thereby promoting T-cell persistence. Additionally, CARGO’s proprietary Regulated Cytokine Drive is a genetic tool that can be incorporated into the CAR T-cell therapy to control cytokine signaling to boost T-cell activity and persistence.
As tumors evolve to resist treatment, novel approaches must be employed to overcome common resistance mechanisms. CARGO’s STASH/GAS platforms enable the engineering of next-generation, multi-specific and multi-functional CAR T-cell therapies that can overcome multiple cancer resistance mechanisms. Engineering next-generation therapies with enhanced capabilities requires the introduction of genetic “cargo” that can exceed the payload capacity of a single vector, necessitating the use of multiple vectors. However, engineering cells with multiple vectors can result in a heterogeneous cell product—only a portion of which receives all intended vectors.
CARGO’s novel STASH/GAS technology is a robust method for purifying cells engineered with multiple vectors using a single selectable marker. STASH/GAS enables the production of a homogeneous, multiplex CAR T-cell product, which will be necessary for advancing next-generation cell therapies into the clinic. Multi-specific and multi-functional targeting also widens the applicability of this type of treatment to other cancers including solid tumors.
