T-cell Immunotherapies and the Role of Nonclinical Assessment: The Balance between Efficacy and Pathology

Abstract

Gene-engineered T-cell therapies have the potential to revolutionize the treatment of cancer. These therapies have shown exceptional clinical efficacy specifically in the field of B-cell malignancies and the first products (Kymriah™ and Yescarta™) have recently been approved in the United States for specific indications. The power of these treatments is also linked with a distinct set of toxicities both predicted and unpredicted, including off-tumor activity, cytokine release syndromes, and neurotoxicity, occasionally with fatal consequences. As these therapies begin to reach more patients, it is critical to develop the nonclinical tools to adequately determine the mechanisms driving these toxicities, to assess the safety risks of candidate products, and to develop strategies for safety management.

Current Perspectives in Cancer Immunotherapy

“…The MHC restriction especially this of HLA class I molecules which are often downregulated in cancer cells, the dependence on co-receptors such as CD8 and the competition between the transgene receptor and the endogenous TCR for interaction with the available CD3 complex components, usually minimize the therapeutic effectiveness of the approach [236,237]. In addition, the presence of endogenous TCR may allow for chain mispairing between endogenous and introduced TCR a and β chains, leading to reduced receptor expression and often to serious adverse effects propagated by the unpredictable generation of self-reactive TCRs [238,239]. Currently, such “off target, off tumor” effects as the result of TCR chain mispairing or high affinity TCRs recognizing “off target” epitopes, are alleviated by several strategies including among others, codon optimization of the TCR a and β genes and the use of single chain recombinant TCRs [240,241].…”

Targeting Cancer Stem Cells by Genetically Engineered Chimeric Antigen Receptor T Cells

“…Although cancer patients usually undergo lymphocyte depletion regimens, their lymphocyte recovery occurs, developing the various populations of T cells including Tregs that downregulate the antitumor effect accompanied with the transferred CAR T cells, a situation that is not replicated in the mice model (North, 1982;Gattinoni et al, 2005). However, this model has been useful in confirming that CAR T cells are able to target tumors; the obstacles associated with solid cancer microenvironment might be undervalued (Sharpe, 2018). Therefore, animal equivalent products as well as syngeneic tumor models might be more useful in testing CAR T cells' safety and efficacy (Kochenderfer et al, 2010b;Davila et al, 2013).…”

Externally-Controlled Systems for Immunotherapy: From Bench to Bedside

“…In an elegant study, Wang et al developed a strategy to achieve hepatic-specific expression of IL-12 that also responded to the control of MFP. The authors developed an AdV harboring the sequences for GAL4 binding into a hepatic-specific promoter driving the expression of IL-12 ( 6 ). Direct administration of these AdVs enabled controlled hIL-12 expression in the liver for more than 48 weeks when MFP was administered every 24 h. In addition, this system achieved complete tumor regression in an aggressive model of liver metastases in vivo .…”

“…Immunotherapy has drastically evolved since the past 30 years, providing diverse approaches for boosting the intrinsic power of the host's immune system to target different diseases, especially cancer. This field includes a broad spectrum of strategies that includes the administration of cytokines, chemokines, monoclonal antibodies, cell lysates, and living cells (1)(2)(3)(4)(5)(6)(7) to directly or indirectly boost the immune system to fight cancer or to defuse it for mitigating transplant rejection (8), autoimmune diseases (9), or chronic inflammation (10).…”