mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer
Gal Cafri, … , Paul F. Robbins, Steven A. Rosenberg
Gal Cafri, … , Paul F. Robbins, Steven A. Rosenberg
Published October 5, 2020
Citation Information: J Clin Invest. 2020;130(11):5976-5988. https://doi.org/10.1172/JCI134915.
View: Text | PDF
Clinical Research and Public Health Oncology

mRNA vaccine–induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer

Abstract

BACKGROUND Therapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODS We recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients’ tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTS The vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSION This vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATION Phase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDING Center for Clinical Research, NCI, NIH.

Authors

Gal Cafri, Jared J. Gartner, Tal Zaks, Kristen Hopson, Noam Levin, Biman C. Paria, Maria R. Parkhurst, Rami Yossef, Frank J. Lowery, Mohammad S. Jafferji, Todd D. Prickett, Stephanie L. Goff, Christine T. McGowan, Samantha Seitter, Mackenzie L. Shindorf, Anup Parikh, Praveen D. Chatani, Paul F. Robbins, Steven A. Rosenberg

×

Figure 3

Immune monitoring for patient 4251.

Options: View larger image (or click on image) Download as PowerPoint
Immune monitoring for patient 4251. (A) T cells were negatively selected...
(A) T cells were negatively selected from PBMCs and subjected to IVS using either TMG-transfected or peptide-loaded DCs. DCs alone served as a negative control. IVS cultures were then restimulated with DCs loaded with single peptides and tested either by flow cytometry for 4-1BB expression or IFN-γ secretion using an ELISPOT assay. Data from before vaccine administration, after 4 vaccines, and after 7 vaccines following peptide or TMG restimulation are presented. Positive responses were defined as a 3-fold increase in IFN-γ and 4-1BB or OX40 expression above the DMSO control levels. All positive responses are indicated with black arrows. (B) Positive T cell cultures showing at least a 3-fold increase compared with the DMSO sample from A were cocultured for 18 hours with autologous DCs that were loaded with WT or mutated long peptide (Mut). Cells were tested for antigen recognition by flow cytometry evidence of 4-1BB upregulation (results are representative of 1 of 2 experiments).