Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

Amanda L Huff; S Daniel Haldar; Alexander A Gergis; Hejia Henry Wang; Ludmila Danilova; Thatcher Heumann; Maureen Berg; Yuxuan Wang; Lalitya Andaloori; Alexei Hernandez; Gabriella Longway; Benjamin Barrett; Zirui Zhu; Emily Davis-Marcisak; Christopher Thoburn; James Leatherman; Sarah Mitchell; Jae W Lee; Daniel H Shu; Maximillian F Konig; Brian J Mog; Janelle Montagne; Erin M Coyne; Katherine Bever; Marina Baretti; Mark Yarchoan; Robert A Anders; Luciane T Kagohara; Daniel Laheru; Amy M Thomas; Jennifer Durham; Julie M Nauroth; Jiayun Lu; Hao Wang; Elana J Fertig; Won Jin Ho; Nilofer S Azad; Elizabeth M Jaffee; Neeha Zaidi

doi:10.1038/s41467-026-68324-4

Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

Nat Commun. 2026 Feb 10;17(1):1538. doi: 10.1038/s41467-026-68324-4.

Authors

Amanda L Huff^#^{1

2

3}, S Daniel Haldar^#^{1

2

3

4}, Alexander A Gergis^{1

2

3}, Hejia Henry Wang^{1

2

3}, Ludmila Danilova^{1

2

3}, Thatcher Heumann^{1

2

3}, Maureen Berg³, Yuxuan Wang³, Lalitya Andaloori^{1

2

3}, Alexei Hernandez^{1

2

3}, Gabriella Longway^{1

2

3}, Benjamin Barrett^{1

2

3}, Zirui Zhu^{1

2

3}, Emily Davis-Marcisak^{1

2

3

5}, Christopher Thoburn^{1

2

3}, James Leatherman^{1

2

3}, Sarah Mitchell^{1

2

3}, Jae W Lee^{1

2

3

6}, Daniel H Shu⁷, Maximillian F Konig^{3

8

9

10

11}, Brian J Mog^{3

8

9

10

11}, Janelle Montagne^{1

2

3}, Erin M Coyne^{1

2

3}, Katherine Bever^{1

2

3}, Marina Baretti^{1

2

3}, Mark Yarchoan^{1

2

3}, Robert A Anders^{1

2

3}, Luciane T Kagohara^{1

2

3}, Daniel Laheru^{1

2

3}, Amy M Thomas³, Jennifer Durham^{1

2

3}, Julie M Nauroth^{1

2

3}, Jiayun Lu^{1

2

3}, Hao Wang^{1

2

3}, Elana J Fertig⁷, Won Jin Ho^{1

2

3}, Nilofer S Azad^{1

2

3}, Elizabeth M Jaffee^{12

13

14}, Neeha Zaidi^{15

16

17}

Affiliations

¹ Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
⁸ Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Lustgarten Pancreatic Cancer Research Laboratory, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹¹ Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu.
¹³ Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ejaffee@jhmi.edu.
¹⁴ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. ejaffee@jhmi.edu.
¹⁵ Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.
¹⁶ Johns Hopkins Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.
¹⁷ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu.

^# Contributed equally.

Abstract

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

Publication types

Clinical Trial, Phase I

MeSH terms

Adenocarcinoma* / genetics
Adenocarcinoma* / immunology
Adenocarcinoma* / therapy
Adult
Aged
CD8-Positive T-Lymphocytes / immunology
Cancer Vaccines* / administration & dosage
Cancer Vaccines* / adverse effects
Cancer Vaccines* / immunology
Cancer Vaccines* / therapeutic use
Female
Humans
Immune Checkpoint Inhibitors* / administration & dosage
Immune Checkpoint Inhibitors* / therapeutic use
Ipilimumab / administration & dosage
Ipilimumab / therapeutic use
Male
Middle Aged
Mutation
Nivolumab / administration & dosage
Nivolumab / therapeutic use
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / therapy
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / immunology

Substances

Cancer Vaccines
Proto-Oncogene Proteins p21(ras)
KRAS protein, human
Immune Checkpoint Inhibitors
Nivolumab
Ipilimumab

Associated data

ClinicalTrials.gov/NCT04117087

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding