Author: Kirsteen Maclean Ph.D.
Over the past decade cellular therapies have transformed the field of oncology, offering new hope to cancer patients. With its ability to activate and harness the power of the immune system to target cancer cells directly, Chimeric Antigen Receptor (CAR)-T therapy has demonstrated remarkable efficacy particularly in a subset of hematological diseases and has the potential to shape the future of cancer treatment. However, while treatment with CAR-T cells has produced remarkable clinical responses with certain malignancies, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors. Barriers to effective CAR-T cell therapy include toxicity, limited activity, antigen escape, restricted trafficking, and infiltration. In addition, we now know that tumor microenvironment (TME) interactions with CAR-T cells critically alter the overall functionality of the CAR-T cell. Several new publications have therefore described novel approaches to CAR- T design using T cells receptor fusion construct (TRuC) that instead harness all signaling subunits of the TCR to activate T cells independently of the peptide-major histocompatibility complex (MHC). These TRuC-T cells are enabled fusion proteins comprising a tumor-antigen binder tethered to full-length CD3ε or γ subunits. Like natural CD3 subunits, the TRuC is assembled into the TCR and reprograms T cells to kill tumor cells expressing the cognate surface antigen. Data have indicated that CD19-targeted TRuC-T cells potently eliminate tumors in mouse models and importantly, release fewer cytokines than existing traditionally designed CD19-targeted CAR-T cells, without the need for an additional co-stimulatory domain1.
Recent work published from the National Cancer Institute Center for Cancer Research, and colleagues in Nature Medicine2 describe phase 1 results from an ongoing phase1/2 trial in patients with refractory mesothelin-expressing mesothelioma (MPM), ovarian cancer (OvC), cholangiocarcinoma (CHO) and non-small cell lung cancer (NSCLC) on utility of the novel T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel). The design consists of a single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Briefly, 20% of the 30 patients who received gavo-cel and were evaluated for a response experienced a 30% or greater reduction in tumor size, as determined by post-treatment imaging. Many of these patients also had a durable tumor regression, continuing for a year post- treatment.
One of the goals of the trial was to gain insight into the potential impact of gavo-cel therapy on the tumor microenvironment (TME), achieved by analyzing pre-treatment and post-treatment biopsies from patients with MPM. MultiOmyxTM technology offered by NeoGenomics was used to evaluate the expression of a custom panel of 14 biomarkers, including TIGIT, CD155, LAG3, CD4, CD56, CD3, CTLA4, CD8, PD-L1, PD-1, FoxP3, CD68 and TIM-3 and tumor segmentation marker PanCK on FFPE samples. Important spatial insight revealed that at baseline, the TME of the responding patient was characterized by an abundance of T cells. At 8 weeks after treatment, T cells were also observed to infiltrate into the tumor area of this responding patient, while expression of the checkpoint marker PD-L1 was also increased. Interestingly, expression of CD155, which functionally interacts with TIGIT, was observed to be high at both baseline and post-treatment in the non-responder. In contrast, levels of CD155 were undetectable at baseline in the responder, with only a minor increase observed after treatment. The authors suggest that Gavo-cel tumor infiltration may result in the remodeling of the TME, with upregulation of immunoinhibitory ligands that may represent a potential mechanism of resistance. With this in mind, the authors have already begun clinical testing of a second-generation mesothelin-targeting TRuC, TC-510. This TRuC is designed to trigger the same mesothelin-targeting immune response as gavo-cel and additionally convert a signal that normally dampens immune activity into an immune activator.
Overall, as noted by the authors, “our data strongly support the development of TRuC-based cell therapies in patients with solid tumors as well as mesothelin as a target. Given the promising preliminary results reported here, a phase 2 study is underway to evaluate the efficacy of gavo-cel in mesothelin-expressing cancers, which will allow for repeat intravenous dosing and the combination with ICI therapy as strategies to promote greater gavo-cel exposure and to prevent exhaustion of the engineered T cells”.
Although many obstacles in the treatment of solid tumors with CAR-T cell therapy remain to be addressed, spatial insight of the complexities of the TME that potentially restricts CAR-T cells activity through the extracellular matrix, suppressive immune cells and cytokines is being increasingly adopted in early phase trials. Future developments within the CAR-T space will likely harness combinatorial strategies that include targeting the TME to overcome the multitude of challenges posed by the tumors.
- Ding et al., 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980471/
- Hassan et al., 2023 https://pubmed.ncbi.nlm.nih.gov/37501016/