Modifiable CAR T Cells Target solid Tumors with more Precision

Good news! Cancer is history (soon)!

"... However, as successful as [CAR T] are in treating some cancers, they fail at treating others, such as pancreatic tumors, which develop clever ways of avoiding immune detection.  ...
In two new mouse studies ... researchers unveiled tactics for creating manipulatable CAR T cells. The researchers behind the works say that, thanks to the new approaches, they may be able to overcome the current hurdles facing CAR T therapies. The new techniques allow them to control when and where CAR T cells are active, targeting tumors at specific times and keep CAR T cells from becoming less effective over time, which often happens during cancer. ..."

From the introduction and abstract:

"T cells with modified receptors that recognize tumor antigens (chimeric antigen receptor or CAR T cells) have proved effective in treating B cell malignancies, but solid tumors create an immunosuppressive microenvironment that limits their function. To overcome this limitation, Allen et al. enhanced engineered T cells with a second synthetic receptor that could recognize a tumor antigen and cause the T cell to secrete the cytokine interleukin-2 (see the Perspective by Salazar-Cavazos and Altan-Bonnet). Interleukin-2 promoted local proliferation of the T cells despite the tumor’s immunosuppressive effects. Such engineered cells allowed effective treatment of solid tumors in mouse models. ...

Structured Abstract

INTRODUCTION

Many solid tumors fail to respond to T cell therapies because their immunosuppressive microenvironment blocks T cell infiltration, activation, and proliferation. Major tumor suppression mechanisms include inhibition of T cell receptor (TCR) signaling and consumption of inflammatory cytokines. Overcoming the suppressive tumor microenvironment remains a major barrier to solid tumor immunotherapy.

RATIONALE

Supplementing T cell activity with inflammatory cytokines, such as high-dose Interleukin-2 (IL-2) has long been known to drive potent antitumor function. Systemic IL-2 treatment, however, has proven prohibitively toxic by causing severe adverse effects including capillary leak syndrome and eventually end-organ dysfunction. Cell autonomous cytokine production has the potential to overcome these toxicities by delivering cytokine locally and directly to a tumor. We engineer therapeutic T cells bearing synthetic cytokine circuits in which a tumor-specific synthetic Notch (synNotch) receptor drives IL-2 production. These tumor-targeted IL-2 delivery circuits offer a potential way to locally overcome tumor suppression while minimizing systemic IL-2 toxicity.

RESULTS

We observed that engineered synNotch→IL-2 induction circuits drove potent infiltration of chimeric antigen receptor (CAR) or TCR T cells into immune-excluded tumor models of pancreatic cancer and melanoma. This improved infiltration was associated with significantly improved tumor clearance and survival in these challenging immune-competent tumor models. Unlike systemically delivered IL-2, the local cell-based IL-2 circuit does not show toxicity as these synNotch→IL-2 circuits are not dependent on TCR/CAR activation but are still tumor-targeted.

However, the exact mechanism used to deliver IL-2 proved to be critical. CAR T cells with SynNotch-induced IL-2 circuits led to far better antitumor efficacy compared with CAR T cells engineered with constitutive IL-2 expression or TCR/CAR–induced IL-2 expression (e.g., from an nuclear factor of activated T cells (NFAT) promoter). Furthermore, we found that autocrine production of IL-2, where the same T cell expresses the CAR/TCR and synNotch→IL-2 circuit, proved to be critical. Paracrine delivery of IL-2, where a CAR T cell is supported by a separate T cell with a synNotch→IL-2 circuit, proved ineffective in the presence of competing native IL-2 consumer cells, such as host regulatory T cells or bystander T cells.

High-dimensional immune profiling shows that the IL-2 synthetic cytokine circuits act primarily on T cell populations without causing significant changes to other immune cell compartments. The tumors show significantly increased infiltration of both the CAR T cells and host bystander T cells. Nonetheless, only the antitumor CAR T cells show enhanced markers of activation, proliferation, and cytotoxicity, as well as reduced markers of exhaustion.

We hypothesize that these circuits are effective because they bypass requirements for TCR/CAR activation and provide IL-2 in a more potent autocrine configuration. These features thereby allow the engineered T cell to overcome the main modes of tumor immune suppression: inhibition of TCR signaling and competitive cytokine consumption. These engineered T cells appear to act as pioneers, triggering expansion in the tumor through their synNotch-induced IL-2 production, which then cooperatively enables the initiation of sustained CAR/TCR-mediated T cell activation and killing.

CONCLUSION

These results show that it is possible to reconfigure T cell circuits to reconstitute the key outputs required for a robust antitumor response (CAR/TCR activation and inflammatory cytokine signaling), but in a manner that bypasses the critical points of tumor immune suppression. These types of engineered local cytokine delivery circuits may thereby provide a potential general strategy for driving effective T cell activity against immune-suppressed solid tumors."

From the abstract:

"Synthetic gene circuits that precisely control human cell function could expand the capabilities of gene- and cell-based therapies. However, platforms for developing circuits in primary human cells that drive robust functional changes in vivo and have compositions suitable for clinical use are lacking. Here, we developed synthetic zinc finger transcription regulators (synZiFTRs), which are compact and based largely on human-derived proteins. As a proof of principle, we engineered gene switches and circuits that allow precise, user-defined control over therapeutically relevant genes in primary T cells using orthogonal, US Food and Drug Administration–approved small-molecule inducers. Our circuits can instruct T cells to sequentially activate multiple cellular programs such as proliferation and antitumor activity to drive synergistic therapeutic responses. This platform should accelerate the development and clinical translation of synthetic gene circuits in diverse human cell types and contexts."

“Smarter” CAR T Cells Target Tumors with Precision | The Scientist Magazine® Two studies in mice now show that researchers can control when and where CAR T cells are active, potentially overcoming previous hurdles for CAR T–based treatments.

Designer lymphocytes expand the dynamic range of possibilities for treating disease (no public access) Designer lymphocytes expand the dynamic range of possibilities for treating disease

Synthetic cytokine circuits that drive T cells into immune-excluded tumors (no public access)

Multidimensional control of therapeutic human cell function with synthetic gene circuits (no public access)