Review Sees Potential in CAR T-Cell Therapy for Pancreatic Cancer

Despite current challenges in targeting pancreatic cancer with CAR T-cells, novel targets and strategies hold promise in this difficult disease setting.

Currently, there are limited effective treatment options for pancreatic cancer—an aggressive disease that often presents in late stages when it is already locally advanced or involves metastases. One potential path forward in pancreatic cancer treatment is chimeric antigen receptor (CAR) T-cell therapy, which has had limited efficacy in this disease setting thus far, but is being studied in clinical trials. A recent review published in Molecular Therapy - Oncolytics highlighted ongoing trials of CAR T-cell therapy in pancreatic cancer and what the future may hold.

In pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of pancreatic malignancies, there has been little progress in survival rates in recent years. As it stands, PDAC is on track to become the second leading cause of cancer-related deaths by 2030 if no significant improvements in treatment efficacy are made. Surgical removal is the only potentially curative treatment, but most patients are not eligible by the time it is detected.

Next-generation and single-cell sequencing have provided insight into the mechanisms of PDAC and assisted researchers and clinicians in determining potential targeted therapy approaches. However, only limited subgroups of patients have tumors with mutations that can be targeted. Therefore, these advances have not led to significant improvements in overall survival.

In recent years, immunotherapies such as CAR T-cell therapy have improved outlooks in other cancer types, especially hematological malignancies. In CAR T-cell therapy, T cells are extracted and engineered to target and kill malignant cells. There are 5 CAR T-cell therapies currently approved, but all are only approved for hematological cancers.

In PDAC, past trials of CAR T-cell therapy have not been as successful. In a selection of published studies, only a limited subset of patients achieved stable disease, and most only saw short-term responses or disease progression. In current trials, a variety of agents targeting different antigens are being investigated.

One of the most researched antigens is mesothelin (MSLN), a protein that is overexpressed in many solid tumors. Pre-clinical murine studies have shown MSLN-targeted CAR T-cell therapy to reduce tumor burden and prolong survival, and phase 1 trials in patients with PDAC have found it a tolerable and potentially effective strategy as research continues.

The transmembrane glycoprotein CD133 is another potential target that is highly expressed in PDAC stem cells as well as in other cancers. A phase 1 trial including 7 patients with advanced pancreatic cancer with tumors showing 50% or greater CD133 expression found that CD133-targeted T cells were effective in some cases, with 3 patients achieving stable disease, 2 partial remission, and 2 disease progression. CD133 was not seen in biopsies after treatment, suggesting any cells positive for CD133 were eradicated.

In a phase 1 trial targeting epidermal growth factor receptor (EGFR), a transmembrane protein, half of the 16 individuals with PDAC achieved stable disease for 2-4 months, 4 had partial response, 2 had disease progression, and 2 were lost in follow-up. The treatment was determined safe and somewhat effective, but EGFR is a wide target that is expressed in a variety of tissues, which could lead to adverse effects.

Another potential target, human epidermal growth receptor 2 (HER2), is highly expressed in up to 60% of patients with PDAC. The risk for on-target but off-tumor toxicity is high with HER2-targeted treatment, however. Two individuals treated with HER2-targeted CAR T-cell therapy achieved stable disease for 5.3 and 8.3 months in one phase 1 trial.

In solid tumors, there are several limiting factors for CAR T-cell efficacy, including:

  • the inability of T cells to efficiently traffic to tumor sites and infiltrate the tumor
  • the limited array of targetable antigens and heterogeneous antigen expression
  • the limited fitness and survival of CAR T cells prior to reaching the tumor site
  • the immunosuppressive tumor microenvironment (TME)

PDAC has a unique TME that makes it a challenging disease for CAR T-cell treatment, because identifying an ideal target to limit tumor resistance and effectively treat PDAC is difficult.

Several strategies may help overcome the challenges associated with CAR T-cell therapy in PDAC treatment. Given the difficulties with infiltration, locoregional or intratumoral delivery might help bypass the PDAC TME according to results seen in mouse models. Armored CAR T-cells designed to withstand the TME are another potential option. CAR T-cells that target multiple antigens and combination therapies might also prove effective.

Autologous CAR T-cells are currently the norm, but allogeneic cells from healthy donors have potential to reduce the notoriously high costs of production, could be available immediately, and would be standardized compared with autologous CAR T-cells. Other potential alternatives are allogeneic natural killer CAR T-cells, which are part of the innate immune system and target foreign or damaged cells without prior sensitization; and tumor-infiltrating lymphocytes, which are being tested in phase 1 and 2 clinical trials in PDAC.

“The current challenges in translating successful CAR T-cell therapies from hematological to solid tumors are slowly being overcome by several strategies designed to adapt and overcome the barriers within the TME,” the authors wrote. Overall, despite the current limits in CAR T-cell efficacy, the review authors see it as an active and promising strategy for PDAC that may lead to improved response and survival rates.

Reference

Yeo D, Giardina C, Saxena P, Rasko JEJ. The next wave of cellular immunotherapies in pancreatic cancer. Mol Ther Oncolytics. Published online February 1, 2022. doi:10.1016/j.omto.2022.01.010