Yale scientists energize CAR-T cancer immunotherapy by hitting the gas on metabolism

Scientists at Yale University have found a way to enhance the cancer-killing power of CAR-T cells by reprogramming an amino acid metabolism pathway. The discovery could guide the development of cell therapies with improved tumor control, the researchers said, and potentially enable them to treat more cancer types.

By using the CRISPR gene-editing tool, the Yale scientists found that dialing up the expression of the PRODH2 gene, which is involved in proline metabolism, could boost the function for CD8+ T cells. CAR-T cells engineered with PRODH2 showed improved killing of cancer cells in several mouse models including of breast cancer. The findings were published in the journal Cell Metabolism.

Solid tumors have proven difficult for CAR-T cells to target partly because hostile tumor microenvironments can suppress the immune activity and metabolism of T cells. PRODH2, therefore, represents an interesting target as part of a multi-pronged strategy to enhance CAR-T cells’ strength, especially for solid tumors, the team, led by senior author Sidi Chen, suggests.

Typically, CRISPR is used to silence genes so scientists can observe the consequences of loss of function. But this time, the Yale team used it to add genes in a genome-wide screen to find potential targets that can boost T-cell function.

The researchers identified several genes, which upon increased expression, can enhance CD8+ T cell function. They zeroed in on PRODH2 because T cells with it proliferated much faster than control T cells and showed lower levels of programmed cell death. PRODH2 is usually not expressed in immune cells, which could explain why it wasn’t identified in prior gene-silencing screens.

To test whether increasing PRODH2 expression can enhance T cells’ cancer-killing ability, the scientists co-engineered the enzyme with CARs that can recognize CD22, BCMA and HER2 and designed similar CARs but with a prematurely stopped PRODH2 gene coding region as control.

In a mouse B-cell leukemia model, CD22 CAR-T cells with PRODH2 showed significantly stronger antitumor activity than control CAR-T cells did; the PRODH2 cells were more effective at controlling the disease in terms of tumor burden and animal survival, the team reported.

CAR-T cells bearing PRODH2 also led to better responses in mouse models of BCMA multiple myeloma and HER2 breast cancer compared with their counterparts.

Further analysis showed that adding PRODH2 dialed up multiple genes that are directly related to T-cell function including T-cell activation, signaling and effector function. The CAR-T cells also displayed a metabolism profile that’s been linked to better persistence during cancer immunotherapy.  

The landmark success of CD19-targeted CAR-T cell therapies such as Gilead Sciences’ Yescarta has revolutionized the treatment of some blood cancers. But many challenges remain for this type of immunotherapy, especially in solid tumors.

In exploring ways to enhance CAR-T therapy, scientists at the Fred Hutchinson Cancer Research Center found that adding components in the CD3 protein complex to a CAR could improve the antigen sensitivity and activation of CAR-T cells.

Other promising approaches include adding stimulatory elements to the CAR. A research team at City of Hope, for one, will report findings at the upcoming American Association for Cancer Research annual meeting that incorporating interleukin-12 to an anti-TAG72 CAR could significantly improve antitumor response of the CAR-T cells against ovarian cancer in mice.

The tumor microenvironment can be metabolically challenging for T cells to survive, so approaches like increasing PRODH2 expression to enhance T-cell metabolism may improve T-cell antitumor immunity, the Yale team said. Plus, the CRISPR screen approach could be used to identify other T-cell boosters, the team said.

It’s worth noting that in the current study, the anticancer effect of PRODH2 HER2-CAR-T cells in breast cancer was still not as striking as their CD22- or BCMA-CAR-T counterparts in their respective blood cancer models. The result indicates that while PRODH2 could be leveraged to enhance CAR-T efficacy, it might not be the solution to the solid tumor problem on its own.