Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers

Abstract

Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well in vitro , but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the ex vivo manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell defi cits can be seen at diagnosis as well, implying immune defi cits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.

Cellular therapy: Immune‐related complications

“…In CLL, trials have shown that effectiveness of the CD19 directed CAR‐T is dependent on the intrinsic T‐cell function itself . Similar observations on intrinsic T‐cell factors affecting CAR‐T efficacy have been recently made in the pediatric population as well . Patients with robust T‐cell proliferation and activation had improved CAR‐T responses compared to patients without good responses.…”

“…been recently made in the pediatric population as well. 26 Patients with robust T-cell proliferation and activation had improved CAR-T responses compared to patients without good responses. Given the average age of the population with CLL the intrinsic T-cell response is variable and thus effects outcome (Table 1).…”

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…T cells differentiate in a progressive manner from naive T cells (T N ) →T stem cell memory (T SCM ) →T central memory (T CM ) →T effector memory (T EM ) and ultimately terminally differentiated effectors (T EFF ) . Cancer patients frequently are depleted of T N and early memory subsets, which have a superior capacity to proliferate and persist, and develop a reciprocal accumulation of terminally differentiated T EM /T EFF cells. These later subsets are prone to apoptosis and incapable of sustained proliferation.…”

“…They are, in short, incapable of expanding to the magnitude required to induce clinically apparent tumor regression. This situation is compounded in many solid cancer patients by the routine use of cytotoxic chemotherapy and radiation therapy which serves to deplete less‐differentiated T cell subsets . Lastly, the microenvironment of many cancers is enriched in immunosuppressive cell subsets, including T regulatory cells, aberrantly matured myeloid cells, and immunosuppressive populations of fibroblasts …”

“…This situation is compounded in many solid cancer patients by the routine use of cytotoxic chemotherapy and radiation therapy which serves to deplete less-differentiated T cell subsets. [24][25][26] Lastly, the microenvironment of many cancers is enriched in immunosuppressive cell subsets, including T regulatory cells, aberrantly matured myeloid cells, and immunosuppressive populations of fibroblasts. 27 Each of these limiting variables may in principle be overcome using adoptive cell transfer (ACT).…”