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

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Figure 5

Immune monitoring for patient 4271.

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Immune monitoring for patient 4271. (A) T cells were negatively selected...
(A) T cells were negatively selected from PBMCs, and IVS was performed 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 upregulation or by ELISPOT assays for IFN-γ secretion. Data are presented for before vaccine administration, after 4 vaccines, and after 8 vaccines following peptide restimulation. Positive responses were defined as a 3-fold increase in IFN-γ and 4-1BB or OX40 expression above the DMSO control level. 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 level from A were cocultured for 18 hours with autologous DCs that were loaded with WT or mutant long peptides. Cells were tested for antigen recognition by flow cytometry for 4-1BB expression (results are representative of 1 of 2 experiments). (C) Neoantigen-specific cells were restimulated and sorted according to 4-1BB upregulation into 96-well plates for single-cell TCR sequencing. PBMCs were collected before and after vaccination and sent for TCR VB sequencing. The data show the frequency of neoantigen-specific cells before and after vaccination.