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Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

Abstract

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

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Fig. 1: Pathological response after neoadjuvant ICI.
Fig. 2: Immune gene signatures, IFN-γ score and TLSs in predicting response to checkpoint blockade.
Fig. 3: TCR clonality, CD8+ TCI, T cell phenotyping and PD-L1 expression.
Fig. 4: Comparisons between pMMR responders and nonresponders for subsets of infiltrating T cells, TCR clonality, CXCL13 expression, IFN-γ score, TMB and TGF-β signatures.
Fig. 5: Recognition of dMMR or pMMR CC organoids by autologous T cells.

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Data availability

The RNA- and DNA-sequencing data will be deposited into the European Genome–Phenome Archive under accession no. EGAS00001004160 and will be made available on reasonable request for academic use and within the limitations of the provided informed consent. Every request will be reviewed by the institutional review board of the NKI; the researcher will need to sign a data access agreement with the NKI after approval. The TCR-sequencing data that support the findings of the present study are available from Adaptive Biotechnologies; however, restrictions apply to the availability of these data, which were used under license for the present study and are not publicly available. However, data are available from the authors on reasonable request and with the permission of Adaptive Biotechnologies.

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Acknowledgements

We thank all patients and their families for participating in the present study. We thank: the Core Facility of Molecular Pathology and Biobanking, L. Braaf, S. Cornelissen and D. Peters for their support in processing of samples; C. Van Rooijen for setting up CD8/PD-1 co-stains; R. Kerkhoven and the Genomics Core Facility for their support with sequencing; the Flow Cytometry Core Facility for their support in flow cytometry; J. Lips from Adaptive Biotechnologies for his support; L. Al-van Wijck from the scientific administration department for data management; L. Hoes, F. Weeber, J. Westra, S. Visser and S. Kaing for facilitating sample acquisition and processing; A. Van der Leun for support in TIL isolation; T. Korse, M. Lucas and E. Platte for PBMC acquisition and processing; A. Atsma, P. Bottenberg, S. Oosterloo, M. van Wijngaarden, P. Den Hartog and S. Dokter for patient care; M. Mok, I. Honing, M. Van Nes and N. De Jong for patient care in the OLVG; P. Drillenburg for sample acquisition; Merus for provision of anti-PD-1 for in vitro experiments; M. Toebes, X. Kong and M. Ligtenberg for the lentiviral HLA-A2 vector and MART-1 peptide; S. Vanhoutvin for legal support; A. Evans, D. Tauriello, G. Sonke and H. Van Tinteren for scientific input. The present study was funded by the BMS International Immuno-Oncology Network and sponsored by the NKI. The funding source had no role in design and execution of the study, data analysis or writing of the manuscript.

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Authors and Affiliations

Authors

Contributions

M.C. designed the trial, coordinated trial procedures, analyzed and interpreted clinical and translational data and wrote the manuscript. L.F.F. performed and interpreted bioinformatics analyses. K.K.D. and V.V. performed organoid experiments. J.G.V.d.B. and P.S. performed the histo- and immunopathological scoring. A.G.A., G.L.B., N.F.K. and H.A.M. informed patients and performed surgery. M.L.-Y. and K.S. performed statistical analyses. C.G. and M. Kuiper were responsible for patient care. M. Maas and R.G.B.-T. revised CT scans. M. Mertz set up digital quantification of IHC staining. G.B. performed CMS subtyping. A.B. provided input on IHC staining. E.N. was the clinical projects manager. W.H.V., T.R.d.W. and M.E.V.L. performed endoscopies. A.U.v.L. informed and referred patients. M. Kok provided scientific input during protocol writing and design of the study. M.C., T.N.S., E.E.V. and J.B.H. made the experimental plan of investigation. The manuscript was written by M.C. in collaboration with co-authors, who vouch for the accuracy of the data reported and adherence to the protocol. All authors edited and approved the manuscript.

Corresponding authors

Correspondence to Myriam Chalabi or Emile E. Voest.

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Competing interests

L.F.F., K.K.D., J.G.V.d.B., A.G.A., M.L.-Y., K.S., C.G., G.L.B., P.S., M. Mertz, V.V., G.B., A.B., R.G.B.-T., T.R.d.W., A.U.v.L., H.A.M., M. Maas, E.N., N.F.K., W.H.V., A.U.v.L., M. Kuiper and M.E.V.L. have no competing interests to declare. M.C. reports funding to the institute from BMS and Roche/Genentech and an advisory role for BMS, outside the submitted work. M. Kok reports funding to the institute from BMS, Roche/Genentech, AZ and an advisory role for BMS and Daiichi Sankyo, outside the submitted work. J.B.H. reports institutional fees for advisory roles from BMS, Merck, Roche, Neon therapeutics, Pfizer and Ipsen and NKI, and received grants from BMS, Merck, Novartis and Neon Therapeutics, outside the submitted work. E.E.V. reports research funding from BMS, outside the submitted work. T.N.S. is a consultant for Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech; Grant/Research support are from: Merck, Bristol-Myers-Squibb, Merck KGaA; stockholder in: AIMM Therapeutics, Allogene Therapeutics, Neon Therapeutics, all outside the submitted work.

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Peer review information Javier Carmona was the primary editor on this article, and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Study design.

Patients with dMMR or pMMR colon cancers were screened after signing informed consent. Maximum duration from informed consent to surgery was 6 weeks. All patients underwent an endoscopy to obtain biopsies. Shortly thereafter, treatment was started (and patients with pMMR tumors randomized to celecoxib yes/no). Numbers shown refer to the total number of patients to be included per subgroup in this ongoing study.

Extended Data Fig. 2 Consort Diagram.

Patient numbers refer to included patients at the time of data cut-off. *Patient in the run-in period with 2 tumors is accounted for as 1 patient in the eligibility assessment in the dMMR group.

Extended Data Fig. 3 Characteristics of T-cell infiltration in pMMR and dMMR tumors.

Panel a, Changes in CD3+ T cell infiltration in pMMR tumors (left, n=13) and dMMR tumors (right, n=19). Boxplots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no further than 1.5 * IQR from the hinge. Pre-to-post pairwise statistical significance was tested with a Wilcoxon Signed-Rank test; for differences between pMMR and dMMR significance was tested using a Wilcoxon Rank-Sum test. All statistical tests were two-sided. Panel b, Changes in FOXP3 T cell infiltration in pMMR tumors (left, n=13) and dMMR tumors (right, n=19). Boxplots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no further than 1.5 * IQR from the hinge. Pre-to-post pairwise statistical significance was tested with a Wilcoxon Signed-Rank test; for differences between pMMR and dMMR significance was tested using a Wilcoxon Rank-Sum test. All statistical tests were two-sided. Panel c, Tumor mutational burden (absolute number of mutations by summation of coding non-synonymous single nucleotide variants and frame-shifting indels) in dMMR (left, n=19) vs. pMMR (right, n=15) tumors. Boxplots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no further than 1.5 * IQR from the hinge. For differences between dMMR and pMMR, statistical significance was tested with a Wilcoxon Rank-Sum test. All statistical tests were two-sided. Panel d, Sum of intratumoral frequency of T cell clones shared between tissue and peripheral blood. Left: pre-treatment and Right: post-treatment comparisons between dMMR (n=6), pMMR responders (pMMR-R, n=3) and pMMR non-responders (pMMR-NR, n=5). Boxplots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no further than 1.5 * IQR from the hinge. Pairwise statistical significance was tested with a Wilcoxon Rank-Sum test, while for comparisons between multiple groups a Kruskal-Wallis test was used. All Wilcoxon statistical tests were two-sided. Panel e, CD68 positivity shown in pixel counts as a percentage of total pixel count. Left: pre-to-post treatment changes in pMMR (n=13) and Right: dMMR (n=19) tumors. Boxplots represent the median, 25th and 75th percentiles; the whiskers extend from the hinge to the largest value no further than 1.5 * IQR from the hinge. Pre-to-post pairwise statistical significance was tested with a Wilcoxon Signed-Rank test; for differences between pMMR and dMMR significance was tested using a Wilcoxon Rank-Sum test. All statistical tests were two-sided. Panel a-e: No adjustments were made for multiple comparisons.

Extended Data Fig. 4 Organoid – T cell co-cultures.

Panel a, Quantification of IFNγ production by CD4+ T cells, obtained by two-week co-culture with autologous tumor organoids, upon stimulation with CC organoids. pMMR non-responders are indicated in dark blue(n=6), pMMR tumor with 30% regression in light blue (n=1), dMMR responders in red (n=5). Number of biologically independent experiments: N3 (n=3); N12 (n=4); N38 (n=1); all other samples (n=2). Background (spontaneous IFNγ production) is subtracted from organoid-induced IFNγ production. Error bars reflect mean + s.e.m. Panel b, Representative flow cytometry histograms of cell surface MHC-I expression of CC organoids after 24-hour pre-stimulation with 200 ng/mL IFNγ. Experiment was performed once. Panel c, Cell surface MHC-I expression of CC organoids with or without 24-hour pre-stimulation with 200 ng/mL IFNγ. Median fluorescence intensitity (MFI) of isotype subtracted from signal. pMMR – IFNγ (n=7); dMMR – IFNγ (n=4); pMMR + IFNγ (n=11); dMMR + IFNγ (n=7). Error bars reflect mean + s.e.m. Panel d, Representative flow cytometry plots of CD8+ T cells tested for tumor reactivity, after two weeks of co-culture with autologous colon cancer (CC) organoids. Number of biologically independent experiments: N12 (n=4); N26 (n=2). Panel e, Quantification of cell surface HLA-A2 expression by flow cytometry of HLA-A2-transduced dMMR (n=2) and pMMR (n=2) CC organoids. Number of biologically independent experiments: N3_pMMR (n=8); N3_dMMR (n=13); N10_dMMR(n=4), N11_pMMR(n=4). Error bars reflect mean ± s.e.m. Panel f, Gating strategy used in tumor reactivity assays.

Extended Data Fig. 5 Peripheral expansion of intra-tumoral T cells.

For 14 tumors (5 dMMR responders, 5 pMMR non-responders and 4 pMMR responders) in 13 patients, T cell receptor (TCR) sequencing was performed on pre- and post-treatment peripheral blood as well as tissue from both timepoints. Figures per patient show the top 10 most frequent intratumoral clones that undergo expansion in peripheral blood post-treatment. Data are shown as the percentage of total TCR reads. (Number of patients and tumors is not equal due to one patient with a double tumor (NICHE-3_dMMR, NICHE-3_pMMR).

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Chalabi, M., Fanchi, L.F., Dijkstra, K.K. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 26, 566–576 (2020). https://doi.org/10.1038/s41591-020-0805-8

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