Advancing CAR-T Therapy: CAR-T Challenges and Horizon (Part 2)

The development of CAR-T therapies faces challenges such as limited efficacy, toxicities, antigen escape, and reduced persistence of CAR-T cells.

In the previous article, we explored the major milestones in CAR-T development and clinical approval, autologous, allogeneic and in vivo CAR-T approaches.

This second blog explores CAR-T challenges and how humanized mice models serve as an highly translational in vivo preclinical system to explore these aspects of CAR-T development.

Challenges in CAR-T development

While CAR-T cell therapies have shown remarkable success in treating hematological malignancies, they continue to face challenges in clinical trials:

• Lack of efficacy: CAR-T cell therapies may not achieve the desired therapeutic effect in all patients. This can be due to various factors such as insufficient expansion or persistence of CAR-T cells, inadequate tumor targeting (suboptimal antigen or neoantigen candidates), or the development of resistance mechanisms by the tumor cells
• Toxicities and adverse Events: CAR-T cell therapies can lead to severe and life-threatening toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. These toxicities can limit the dose and duration of CAR-T cell therapy, impacting its effectiveness
• Antigen escape: Tumor cells can develop mechanisms to evade CAR-T cell recognition by downregulating or losing the target antigen. This can result in treatment resistance and disease relapse
• Limited persistence: CAR-T cells may not persist in the body for a sufficient duration to maintain a durable response. The persistence of CAR-T cells is crucial for long-term tumor control
• Immunosuppressive tumor microenvironment: The tumor microenvironment can hinder CAR-T cell infiltration function and limit their ability to effectively target and eliminate tumor cells. Overcoming TME-imposed restrictions is particularly important for solid tumors as clinical trials are yet to yield new non-hematological approvals
• Heterogeneity of patient population: Clinical trials often include patients with diverse characteristics, such as different tumor types, disease stages, and prior treatments. This heterogeneity can impact the overall response rates and complicate the interpretation of trial results

Leveraging human immune system mice for CAR-T development

Humanized mice, a term denoting immunodeficient mice engrafted with a human immune system are currently revolutionizing the immuno-oncology landscape. As they can be co-engrafted with hematological or solid cancers, they have proven to be a predictive preclinical platform for the investigation of novel CAR-T therapies (among other cancer therapies) and allow predictive insights into the following key aspects of CAR-T development:

1. Safety: In humanized mouse models, CAR-T cell interactions with the human immune system can be monitored closely. This includes evaluating the major side-effects of CAR-T therapies seen in patients, i.e. cytokine release syndrome, neurotoxicity (and graft-versus-host disease in allogeneic CAR-Ts), which can be challenging to model in traditional mouse models
2. Pharmacokinetics and biodistribution: Humanized mouse models can provide insights into the pharmacokinetics and biodistribution of CAR-T cells in vivo. This information is crucial for optimizing dosing regimens and understanding the persistence and trafficking of CAR-T cells within the body
3. Tumor microenvironment infiltration, activation, and bypassing immunosuppression: The tumor microenvironment in humanized mice includes interactions with stromal cells, immune cells, and extracellular matrix components. This enables researchers to assess the ability of novel CAR-T features to infiltrate the tumor and overcome immunosuppression, thus facilitating the assessment of target identification, CAR design, phenotypic switching and broader impact on the local immune (including native and innate) status
4. Efficacy and mechanisms: Humanized mouse models allow researchers to evaluate the efficacy and mechanisms of CAR-T cell therapies in a more physiologically relevant environment (with human disease, human immune system, and human therapy) at high cellular and temporal resolutions (through readouts such as flow cytometry, local and circulating cytokine quantification in addition to gross observations on tumor burden) before moving to clinical trials
5. Combination therapies: Preclinical trials were combinations of CAR-Ts with other immunotherapies (e.g. immune checkpoint inhibitors or bispecific antibodies) or conventional treatments can be easily conducted. These can provide insights into potential synergistic effects and guide the development of combination treatment regimens as well as the identification of cross-indications for existing immunotherapies. Combinational approaches have the potential of reducing tumor evasion against the targeting of individual CAR antigens (such as CD19)
6. Personalized medicine: Humanized mouse models can be engrafted with patient-derived tumor cells and immune cells, allowing for personalized testing of CAR-T cell therapies. This approach can help identify the most effective CAR-T cell product for individual patients and guide treatment decisions

CAR-T therapy has undoubtedly had substantial impact on cancer immunotherapy. At the time of writing this blog (July 2023), there were 1241 active clinical trials for CAR-T therapies, including in non-cancer disease areas such as autoimmune disease (systemic lupus erythematosus and antisynthetase syndrome). As cell engineering, manufacturing processes, understanding of tumor-immune biology, and availability of robust and customizable humanized mouse models continues to improve, CAR technologies are expanding into other immune cell types including NK, NKT, and macrophages, which, together with the next generations CAR-T are poised to continuously to improve outcomes for patients.

Summary

Unraveling the challenges of CAR-T therapy development – such as inconsistent efficacy, adverse effects, antigen evasion, and limited CAR-T cell persistence – this article underscores the promising role of humanized mice models in preclinical research. Despite the hurdles like diverse patient characteristics and a hostile tumor microenvironment, humanized mice, armed with a human immune system, serve as a valuable tool. They allow researchers to explore safety, pharmacokinetics, tumor infiltration, efficacy, combination therapies, and personalized medicine, paving the way for enhanced CAR-T therapies and patient outcomes.

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