Targeting leukemia with the next generation of engineered immune cells: TEGs

Angelo Meringa

Acute myeloid leukemia (AML) remains largely unresponsive to classical immunotherapeutic interventions other than allogeneic stem cell transplantation. Within this context, the major challenge remains the very low mutational load of AML when compared to other diseases, which makes AML initially appear to be less suitable for currently available immune therapies.

An alternative therapeutic opportunity for immune interventions against tumors with low mutational load, such as AML, arises from recent insight that daily cancer immune surveillance is executed not only by abT cells, but by multiple layers of the immune system. One layer consists of gamma delta (gd)T cells, which appears to be more potent than many other subpopulations. The major power of gdT cells arises from the fact that gdT cells see cancer not as a genetic, but as a metabolic disease. In particular, by sensing altered lipid pathways selectively active in cancer cells, gdT cells provide a completely new understanding of the mechanism that the human immune system uses to detect cancer. Most importantly, our group showed that the gdTCR itself is able to distinguish between healthy and malignant leukemic stem cells simply by detecting subtle changes in lipid metabolism and GTPase activities. This resulted in our development of the concept of TEGs (abT cell engineered to express a defined gdTCR). This concept connects the memory and high proliferation capacity of alpha beta (ab)T cells, with the high anti tumor reactivity of a defined gdTCR derived from Vg9Vd2T cells. Due to the lack of HLA-restriction, TEGs provide a promising treatment option for many patients suffering from cancer with low mutational load such as AML, by targeting the RhoB-CD277 axis. Though, we and others most recently defined RhoB-driven spatial and conformational changes of the cell surface protein CD277 as a target for gdTCR, major players impacting this inside out mechanism have not yet been identified. A more precise molecular understanding will allow for improved identification of patients who would benefit from this type of immune therapy. In addition while the first human clinical trials with this concept have been initiated, it remains unclear how efficacy and toxicity of TEGs are balanced, as well as how mechanisms of tolerance active against these most optimized engineered immune cells can be overcome to improve overall efficacy.

To overcome the obstacles of current clinical implementations, we aim to develop risk mitigation plans to increase the chance of clinical success of metabolic cancer targeting through gdTCRs. In short we will:

  1. Improve target definition for TEGs by dissecting the RhoB –CD277 inside out signaling network within the context of primary AML and TEGs.
  2. Elucidate mechanisms responsible for bio-distribution and safety profile of TEGs.
  3. Enhance efficacy of TEGs by breaking mechanisms of immune tolerance.

Aim 1. The GTPase network active in AML blasts will be dissected by array technologies. In addition, compounds that have the potential to modulate the RhoB-CD277 network will be tested within the context of leukemic blasts and TEGs. In Aim 2 we will assess persistence and homing after administration of TEGs in an in vivo model as well as in the human bone marrow niche. We will also assess biology of cytokine release syndrome (CRS) within the human bone marrow niche. In Aim 3 we will assess the impact of immunological help provided by CD4 TEGs for the clearance of leukemic blasts in vivo. We will also explore the therapeutic impact of soluble compounds secreted by the bone marrow stroma as well as by checkpoint inhibitors.

In the current project, we aim to tackle the following major needs for the next generation of metabolic cancer targeting:

  1. Target definition and modulation of the target with defined compounds, which will allow for a more refined identification of patients who could benefit from TEG based therapies.
  2. By studying biodistribution and safety of TEGs, we will identify key compounds responsible for survival, infiltration and cytokine storms mediated by TEGs.
  3. We will identify central mechanisms needed for breaking immune tolerance. E.g. we will be able to identify the needs of the final GMP grade product in terms of CD4 and CD8 ratios, in order to avoid anergy or deletion of transferred immune cells. In addition, these studies will allow us to optimize current clinical trials with readily available clinical checkpoint inhibitors.