Impact of immunological aging on T cell-mediated therapies in older adults with multiple myeloma and lymphoma

Abstract

The treatment landscape for lymphoma and multiple myeloma, which disproportionally affect older adults, has been transformed by the advent of T cell-mediated immunotherapies, including immune checkpoint inhibition, T cell-engaging bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy, during the last decade. These treatment modalities re-enable the patient's own immune system to combat malignant cells and offer the potential for sustained remissions and cure for various diseases.Age profoundly affects the physiological function of the immune system. The process of biological aging is largely driven by inflammatory signaling, which is reciprocally fueled by aging-related alterations of physiology and metabolism. In the T cell compartment, aging contributes to T cell senescence and exhaustion, increased abundance of terminally differentiated cells, a corresponding attrition in naïve T cell numbers, and a decrease in the breadth of the receptor repertoire. Furthermore, inflammatory signaling drives aging-related pathologies and contributes to frailty in older individuals. Thus, there is growing evidence of biological aging modulating the efficacy and toxicity of T cell-mediated immunotherapies.Here, we review the available evidence from biological and clinical studies focusing on the relationship between T cell-mediated treatment of hematologic malignancies and age. We discuss biological features potentially impacting clinical outcomes in various scenarios, and potential strategies to improve the safety and efficacy of immune checkpoint inhibitors, T cell-engaging bispecific antibodies, and CAR-T cell therapy in older patients.

Keywords: Bispecific T cell engager - BiTE; Chimeric antigen receptor - CAR; Hematologic Malignancies; Immunotherapy; T cell.

Figure 1. The interplay between aging and immunity. What is termed “biological age” largely reflects the degree of senescence-associated alterations of an organism’s physiology. Senescence of the immune system is a potential consequence of compensatory immunosuppression due to persistent inflammatory signaling, whereas, at the same time, senescent immune cells contribute to chronic inflammation. As such, inflammatory signaling and senescence fuel each other and constitute the molecular basis of aging. IFN-y, interferon gamma; IL-6, interleukin-6; IL-1, interleukin-1; MHC, major histocompatibility complex; NK, natural killer; TCR, T-cell receptor; TNF, tumor necrosis factor.

Figure 2. Potential interplay between immunological aging and CAR T-cell therapy. Very few data on the impact of immunological aging and CAR-T cell therapy exists, as summarized in the main text. Here, we summarize hypothetical influence of immunological aging and its potential interactions with CAR-T cell therapy, based on small (pre)clinical data. CHIP, clonal hematopoiesis of indeterminate potential; CRS, cytokine release syndrome; CTLA-4, cytotoxic T-lymphocyte-associated Protein 4; ICANS, immune effector cell-associated neurotoxicity syndrome; IL-6, interleukin -6; IL-1ß, interleukin-1ß; LAG3, lymphocyte-activation gene 3; NRM, non-relapse mortality; PD-1, programmed cell death protein 1; TIM-3, T-cell immunoglobulin and mucin domain 3.