Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Rapamycin (rapa) and its analogs show promise in cancer therapy but can inhibit T cell function, limiting their immune-enhancing potential.
• Tumor cells employ immune evasion mechanisms that rapalogs can reverse, potentially facilitating T cell-mediated antitumor responses.
• A key challenge is overcoming rapa's direct immunosuppressive effects on effector T cells to harness its full therapeutic benefit.

Purpose of the Study:

• To investigate if T cells engineered for rapamycin resistance can leverage rapa's immune-modulating effects for enhanced cancer therapy.
• To develop a novel therapeutic strategy combining rapa with rapamycin-resistant chimeric antigen receptor (CAR) T cells targeting B cell malignancies.

Main Methods:

• T cells were genetically modified to express a rapamycin-resistant mutant of mTOR (mTorRR).
• These modified T cells were engineered to express a CAR targeting CD19 (CAR.CD19-28ζ) to direct them against B lymphomas.
• The functionality of mTorRR-expressing T cells was assessed in vitro, including proliferation, cytotoxic activity, and cytokine secretion in the presence of rapamycin.

Main Results:

• T cells expressing transgenic mTorRR maintained mTOR signaling and proliferated in the presence of rapamycin.
• These modified T cells retained cytotoxic function and interferon-γ (IFNγ) secretion, unlike control T cells inhibited by rapamycin.
• The combination of rapamycin and rapamycin-resistant CAR.CD19-28ζ T cells demonstrated superior in vitro antitumor activity against Burkitt's lymphoma and pre-B ALL cell lines compared to either treatment alone.

Conclusions:

• Engineering T cells for rapamycin resistance preserves their effector functions while allowing them to benefit from rapamycin's tumor immune evasion reversal.
• This strategy holds potential as a novel therapeutic approach for B cell malignancies and potentially other cancers.
• Combining rapamycin with rapamycin-resistant CAR T cells represents a promising avenue for overcoming treatment-induced immunosuppression in cancer therapy.