Abstract
Backgroundγ9δ2T cells, which express Vγ9 and Vδ2 chains of the T cell receptor (TCR), mediate cancer immune surveillance by sensing early metabolic changes in malignant leukemic blast and not their healthy hematopoietic stem counterparts via the γ9δ2TCR targeting joined conformational and spatial changes of CD277 at the cell membrane (CD277J). This concept led to the development of next generation CAR-T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. The high affinity γ9δ2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). However, exploring safety and efficacy against a target, which reflects an early metabolic change in tumor cells, remains challenging given the lack of appropriate tools. Therefore, we tested whether TEG001 is able to eliminate established leukemia in a primary disease model, without harming other parts of the healthy hematopoiesis in vivo.MethodsSeparate sets of NSG mice were respectively injected with primary human acute myeloid leukemia (AML) blasts and cord blood-derived human progenitor cells from healthy donors. These mice were then treated with TEG001 and mock cells. Tumor burden and human cells engraftment were measured in peripheral blood and followed up over time by quantifying for absolute cell number by flow cytometry. Statistical analysis was performed using non-parametric 2-tailed Mann-Whitney t-test.ResultsWe successfully engrafted primary AML blasts and healthy hematopoietic cells after 6–8 weeks. Here we report that metabolic cancer targeting through TEG001 eradicated established primary leukemic blasts in vivo, while healthy hematopoietic compartments derived from human cord-blood remained unharmed in spite of TEGs persistence up to 50 days after infusion. No additional signs of off-target toxicity were observed in any other tissues.ConclusionWithin the limitations of humanized PD-X models, targeting CD277J by TEG001 is safe and efficient. Therefore, we have initiated clinical testing of TEG001 in a phase I first-in-human clinical trial (NTR6541; date of registration 25 July 2017).
Highlights
Adoptive cell therapy with engineered immune cells targeting hematological malignancies entered clinical practice [1]
acute myeloid leukemia (AML) Approximately 50% of the primary AML blasts tested so far are susceptible to TEG001 ( [17] and unpublished observation)
We first confirmed activity of TEG001 against the primary AML blasts from multiple donors (Additional file 2: Table S1) by performing an IFNγ ELIspot assay in the presence or absence of 10 μM pamidronate (PAM) while the negative control was not recognized
Summary
Adoptive cell therapy with engineered immune cells targeting hematological malignancies entered clinical practice [1]. Γ9δ2T cells sense molecular stress signatures via the accumulation of intracellular phosphoantigens level on infected and malignant cells [11]. One very attractive and so far, not well-explored alternative to mediate tumor-specific TCR derives from unconventional γ9δ2T cells subsets [10]. This cell subset has the ability to kill tumor cells originating from hematological and solid malignancies in vitro, making it a promising immunotherapeutic option [10, 12]. While several clinical trials have been conducted using ex vivo expanded and adoptively transferred autologous γ9δ2T cells in patients with advanced malignancies including AML, the results showed scarce activity [13]. Alternative strategies are needed for the clinical translation of the strong antitumor reactivity of receptors expressed on γ9δ2T cells [15]
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