Enhancing T Cell Therapy for Solid Tumors with a Novel One-Two Punch Strategy
At the Perelman School of Medicine at the University of Pennsylvania, researchers have made a breakthrough in the battle against solid tumors. Their preclinical study focused on a novel strategy that uses a “one-two punch” to assist T cells in attacking solid tumors. The results of the study, which were reported in the Proceedings of the National Academy of Sciences (PNAS), demonstrated that focusing on two regulators that manage gene activities linked to inflammation caused T-cell expansion in models to be at least ten times higher, increasing antitumor immune activity and durability, showing massive improvements in T cell therapy for solid tumors.
Overcoming the Challenges of CAR T Cell Therapy for Solid Tumors
CAR T cell therapy has been a major game changer in blood cancer therapy and has been revolutionary in personalized cellular therapies. Unfortunately, this type of therapy has remained stubbornly ineffective against solid tumors, such as lung cancer and breast cancer. One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion. In this context, the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an antitumor response.
Targeting Inflammatory Regulators for Enhanced T Cell Potency
Previous observational studies hinted at the potential of the inflammatory regulator Regnase-1 to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells, thereby reviving them to produce an antitumor response. The research team hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further. Disrupting these two regulatory genes in combination produced substantial anticancer effects when compared to individual disruptions. This strategy may be useful in the solid tumor context for boosting the T cell potency in CAR T cell therapy.
The Efficacy of the One-Two Punch Strategy
Using CRISPR-Cas9 gene editing, the team knocked out Regnase-1 and Roquin-1 individually and together in healthy donor T cells with two different immune receptors that are currently being investigated in Phase I clinical trials: the mesothelin-targeting M5 CAR (mesoCAR) and the NY-ESO-1-targeting 8F TCR (NYESO TCR). After CRISPR editing, the T cells were expanded and infused into solid tumor mice models where the researchers observed the double knockout led to at least 10 times as many engineered T cells compared to disabling Regnase-1 alone, as well as increased antitumor immune activity and endurance of the engineered T cells.
Implications for Future T Cell Therapy for Solid Tumors
In solid tumor studies, the limited expansion of CAR T cells has been a common issue. However, knocking out these two non-redundant proteins in combination with T cell therapy may allow each T cell to become more potent, thereby replicating them to greater quantities. This strategy may give T cell therapies a better shot at attacking solid tumors.
In conclusion, this preclinical study has demonstrated that targeting Regnase-1 and Roquin-1 in combination is a worth additional investigation to enhance T cell potency, particularly in the solid tumor context. This “one-two punch” strategy may hold the key to unlock CAR T cell therapy for patients with solid tumors- the most commonly diagnosed cancer types.#cells #therapy #solid #tumours #shows #improvement #Study #Health