Augmented adoptive cell transfer eradicates solid tumors [PreClinical]

1. Combining tumor-specific T cells and pathogen-based immune stimulation, reenergized adoptive cell transfer (ReACT) targeted and eradicated tumor cells in mice.

2. ReACT led to increased migration of activated T cells to the tumors, a metric that correlated with decreased tumor size.

Evidence Rating Level: 2 (Good)

Study Rundown: Because cancer cells can evade being targeted by the body’s immune system, therapies have been developed to alter the tumor’s immune microenvironment. One therapy, adoptive cell transfer (ACT), involves engineering T cells to target cells that express tumor-associated antigens (TAAs). Although this therapy has potential, the tumor microenvironment causes inhibition of T cell function, preventing the therapy’s long-term efficacy. Another approach has been to use pathogens that express TAAs to stimulate the immune system. However, since some tumor cells have altered TAAs, they evade being targeted. In this study, these two approaches were combined into a therapy named ReACT: T cells were engineered to target a TAA as well as a bacterial antigen, and the cells were administered along with a bacterial adjuvant.

When treated with ReACT, a majority of mice with implanted melanoma cells experienced tumor eradication. An increased frequency of T cells in the tumor environment correlated with decreased tumor size. In addition, biomarker levels indicated effective T cell migration and activation. A polyclonal form of ReACT was also tested in a mouse model of melanoma; following tumor eradication in these mice, more tumor cells were introduced but failed to survive, demonstrating an immunological memory response induced by this therapy.

This study demonstrated a new approach for a safer and more efficacious cancer immunotherapy. Future studies will need to more closely mimic a clinical model and provide specific data describing the mechanism of T cell function in this therapy.

Click to read the study in PNAS

Relevant Reading: Cancer Immunotherapy: Strategies for Personalization and Combinatorial Approaches

In-Depth [animal study]: The researchers obtained CD8 T cells that expressed a T cell receptor (TCR) that recognizes a TAA specific to murine melanoma cells. These T cells were then engineered to express a TCR that recognizes the antigen ovalbumin (OVA). In mice with melanoma tumors, this treatment was only effective when the T cells were administered in conjunction with OVA conjugated to Listeria (LM-OVA), a model organism used for pathogen-based cancer vaccines. Seven out of 10 mice experienced complete tumor cell eradication (p<0.001). Neither the engineered T cells alone nor the LM-OVA alone was sufficient to produce significant tumor regression.

Next, the properties and functions of the ReACT T cells were analyzed. The CD8 T cells were present at a higher frequency in the ReACT-treated mice and this value negatively correlated to tumor size, with an r-value of -0.699. These T cells had an activated phenotype, with an increased expression of CD44 and other transcription factors as well as a decreased expression of inhibitory receptors such as CTLA-4. These T cells also had a high expression of CXCR3, a chemokine receptor involved in migration to tumor cells.

Finally, polyclonal ReACT was tested in mice with melanoma tumors. Tumor-specific CD8 T cells were generated by stimulating them with dendritic cells presenting a pool of TAAs; the cells were additionally engineered to express the OVA TCR, and administered to mice along with LM-OVA. Eleven out of 16 mice experienced complete tumor eradication. These mice were then reintroduced to the same melanoma cell line and were resistant to tumor relapse, demonstrating the establishment of an immunological memory response.

Image: PD

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