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A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer


We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study (NCT01312376/UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity.

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Fig. 1: Adoptive transfer of ex vivo-expanded T cells is followed by rapid hematologic reconstitution and clinical benefit.
Fig. 2: Elevated ctDNA levels after ACT are specifically associated with immunogenic mutations.

Data availability

Exome data are available from the European Genome-phenome Archive (EGA) database under accession code EGAS00001002803. The access control to sequence data implemented at the EGA confers patient confidentiality. Cell-free DNA data are available from the European Nucleotide Archive under accession code PRJEB64132 (secondary accession no. ERP149263). The full study protocol is publicly available and provided as Supplementary Protocol. Further information on research design is also available in the Nature Portfolio Reporting Summary linked to this article. Source data are provided with this paper.


  1. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Kandalaft, L. E., Dangaj Laniti, D. & Coukos, G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat. Rev. Cancer 22, 640–656 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med. 10, eaao5931 (2018).

    Article  PubMed  Google Scholar 

  4. Hanker, L. C. et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann. Oncol. 23, 2605–2612 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Bobisse, S. et al. Sensitive and frequent identification of high avidity neo-epitope specific CD8+ T cells in immunotherapy-naive ovarian cancer. Nat. Commun. 9, 1092 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gronlund, B. et al. Should CA-125 response criteria be preferred to Response Evaluation Criteria in Solid Tumors (RECIST) for prognostication during second-line chemotherapy of ovarian carcinoma? J. Clin. Oncol. 22, 4051–4058 (2004).

    Article  PubMed  Google Scholar 

  7. Jimenez-Sanchez, A. et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170, 927–938 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Markman, M. Optimal management of recurrent ovarian cancer. Int. J. Gynecol. Cancer 19, S40–S43 (2009).

    Article  PubMed  Google Scholar 

  9. Goldberg, S. B. et al. Early assessment of lung cancer immunotherapy response via circulating tumor DNA. Clin. Cancer Res. 24, 1872–1880 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xi, L. et al. Circulating tumor DNA as an early indicator of response to T-cell transfer immunotherapy in metastatic melanoma. Clin. Cancer Res. 22, 5480–5486 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kandalaft, L. E., Odunsi, K. & Coukos, G. Immunotherapy in ovarian cancer: are we there yet? J. Clin. Oncol. 37, 2460–2471 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Pedersen, M. et al. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study. Oncoimmunology 7, e1502905 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Laport, G. G. et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood 102, 2004–2013 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Levine, B. L. et al. Large-scale production of CD4+ T cells from HIV-1-infected donors after CD3/CD28 costimulation. J. Hematother. 7, 437–448 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Jamal-Hanjani, M. et al. Detection of ubiquitous and heterogeneous mutations in cell-free DNA from patients with early-stage non-small-cell lung cancer. Ann. Oncol. 27, 862–867 (2016).

    Article  CAS  PubMed  Google Scholar 

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We are grateful to the patients for their dedicated collaboration and the healthy donors for their blood donations. We thank the staff of the biobank at the Center for Experimental Therapeutics, University Hospital of Lausanne, for their assistance. We thank J. Michaux, H.S. Pak and P. Hornitschek-Thielan for their excellent technical assistance. We thank D. Monos and his team from the Children’s Hospital of Philadelphia for high-resolution human leukocyte antigen typing of patients. We thank A.L. Brennan and the staff of the University of Pennsylvania Clinical Cell and Vaccine Production Facility. We thank S. Schuster and J. Svoboda, who supported the study as independent medical monitors at UPenn. The conduct of the clinical study was supported by National Institutes of Health grants R01FD003520, R21CA156224 and P50CA083638 Specialized Program of Research Excellence in Ovarian Cancer (all to G.C.); 5P30 CA016520-36 Abramson Cancer Center of the University of Pennsylvania Core Support Grant (to B.L.L.); and grants from the Marcus Foundation and the Ovarian Cancer Immunotherapy Initiative (both to G.C.). Tumor sequencing was supported by a grant from the Pennsylvania Department of Health (to G.C.; the department specifically disclaims responsibility for any analyses, interpretations or conclusions). All immune analyses were supported by the Ludwig Institute for Cancer Research and grants from the Ovacure Foundation (to G.C. and A.H.), Biltema Foundation, Paul Matson Foundation and Cancera Foundation (to G.C.). The Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics was supported by University of Lausanne/École Polytechnique Fédérale de Lausanne/University of Geneva/University of Bern/Université de Fribourg and the Swiss federal government through the State Secretariat for Education, Research and Innovation.

Author information

Authors and Affiliations



G.C. designed the clinical study and supervised all activities. J.L.T. and E.Z. provided patient care. S.B. and V.B. conducted experiments, and data analysis and interpretation. A.H. developed and supervised the immune analyses. E.M., R.G., B.J.S., C.I., D.B., M.B.-S., D.G. and R.P. performed sequencing, and data analysis and interpretation. A.S., Z.T. and U.D. performed clinical data analysis and interpretation. F.B., A.M., D.D.L., B.L.L., D.J.P.J., D.A.T., S.A.M. and C.H.J. provided additional support to the experiments and data analysis. L.E.K. was responsible for provision of study resources, materials and patient access. S.B., D.E.S., A.H. and G.C. wrote the paper. All authors reviewed, edited and approved the manuscript.

Corresponding author

Correspondence to George Coukos.

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Competing interests

G.C. has received grants and research support from or has been a coinvestigator in clinical trials for Bristol-Myers Squibb, Celgene, Boehringer Ingelheim, Roche, Tigen Pharma, Iovance and Kite. The Lausanne University Hospital (CHUV) has received honoraria for advisory services G.C. has provided to Roche, Genentech, AstraZeneca AG, Bristol-Myers Squibb SA, F. Hoffmann-La Roche AG, MSD Merck AG and Geneos Therapeutics. G.C. is a coinventor in patents in the domains of tumor-infiltrating lymphocyte (TIL) expansion, T cell engineering, antibodies and tumor vaccines. Patents related to the NeoTIL technology from the Coukos laboratory have been licensed by the Ludwig Institute, also on behalf of the University of Lausanne and the CHUV, to Tigen Pharma. G.C. has previously received royalties from the University of Pennsylvania for CAR-T cell therapy licensed to Novartis and Tmunity Therapeutics. E.Z. has received research support from Merck and Co. and honoraria for advisory services from Celldex and Iovance Biotherapeutics. C.H.J. receives royalties paid from Novartis and Kite to the University of Pennsylvania. C.H.J. is a scientific cofounder and holds equity in Capstan Therapeutics, Dispatch Biotherapeutics and Bluewhale Bio. C.H.J. serves on the board of AC Immune and is a scientific advisor to BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Cellcarta, Celldex, Danaher, Decheng, ImmuneSensor, Kite, Poseida, Verismo, Viracta and WIRB-Copernicus group. B.L.L. serves on scientific advisory boards for Akron Bio, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, Thermo Fisher Scientific, Pharma Services, UTC Therapeutics and Vycellix, and is a cofounder and equity holder of Tmunity Therapeutics (Kite) and Capstan Therapeutics. These relationships are managed in accordance with University of Pennsylvania policy and oversight. The remaining authors declare no competing interests.

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Peer review information

Nature Cancer thanks Keith Knutson, Masha Kocherginsk and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 In vitro expansion of cell products and ALC post-ACT.

(A) T-cell expansion over time during product manufacturing. Exp T cells: expanded T cells (n=13). (B-C) Correlation between ALCmax observed post-ACT and lowest ALC value (ALCnadir) observed following lymphodepleting chemotherapy and prior to ACT (B), and between highest ALC value observed post-ACT (ALCmax) and T-cell expansion in vitro (C). R2 and p-values were calculated by simple linear regression analysis.

Source data

Extended Data Fig. 2 Immune subsets in blood.

(A) Main immune subsets in blood of 6 representative patients pre-lymphodepletion (pre-ACT) and one month post-ACT. HD: healthy donor. (B) Frequencies of circulating leukocytes pre-lymphodepletion and one month post-ACT. Paired t-test, two-tailed.

Source data

Extended Data Fig. 3 Intracellular cytokines secretion of neopeptide-specific CD8+ T-cells.

(A) Gating strategy for FACS analysis of ICS assays reported in Fig. 2d. (B) Functional profile of neopeptide-specific CD8+ T-cells post-ACT (n=3 neopeptides, n=2 patients). The pie chart shows the distribution (mean±SEM) of different functionally distinct subsets of neoantigen-specific CD8+ T cells. Individual functions are denoted by arcs. T cells underwent one round of in vitro stimulation followed by CD137-sorting and expansion. After 10 days, they were rechallenged with the specific peptide.

Source data

Extended Data Fig. 4 ctDNA analysis.

(A) Allele frequencies (AF, that is % of mutated reads over total reads) in ctDNA for the 22 single-nucleotide variants (SNVs) for which were able to build a DNA library. Values observed pre- and post-ACT are shown. Variants are color-coded based on their immunogenicity. Variants showing little or no variation between the two time-points are closer to the diagonal line (dotted grey line). Immunogenic variants showed a significant increase in their AF after ACT (P=0.039). This was not observed among Non-Immunogenic mutations (P=0.726). X and y axes are in logarithmic scales. Comparison of AF in cfDNA for immunogenic and non-immunogenic mutations between pre- and post-ACT was performed using paired samples, one-sided Wilcoxon signed-rank test in the R package (v.3.6.1). (B) Estimation of the background noise for each of the SNVs analyzed by ctDNA. Detection of 22 variants in cfDNA with corresponding wild type genes (Supplementary Information). Each gene is reported on one row and it corresponds to annotated immunogenic and non-immunogenic SNVs listed in Extended Data Table 6. Whiskers represent the mean and 99.7% prediction interval (B) or the mean and 95% confidence interval (C). Symbols indicate the AF for each of the 22 mutations detected in cfDNA samples from specific patients, pre-ACT (square) and post-ACT (triangle). We estimated the background distribution through the mean and SD to compute z-score, using a normal approximation for candidate mutations. The ~99.7% prediction interval was standardly defined as a range of 3SD and corrected for aberrant whiskers below zero. P-values were defined as the tail probability and corrected for multiple testing using a Bonferroni correction. Only values with P<0.05 were considered as significantly detected.

Source data

Extended Data Table 1 Patients description
Extended Data Table 2 T-cell products
Extended Data Table 3 Adverse Events
Extended Data Table 4 Neopeptide recognition landscape
Extended Data Table 5 Neopeptide characteristics
Extended Data Table 6 ctDNA analysis

Supplementary information

Supplementary Information

Supplementary Figs. 1–5, Tables 1 and 2 and legends.

Reporting Summary

Supplementary Data 1

Source data for Supplementary Figs. 1–5.

Supplementary Protocol

Clinical study protocol.

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 1

Statistical source data.

Source Data Extended Data Fig. 2

Statistical source data.

Source Data Extended Data Fig. 3

Statistical source data.

Source Data Extended Data Fig. 4

Statistical source data.

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Bobisse, S., Bianchi, V., Tanyi, J.L. et al. A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer. Nat Cancer 4, 1410–1417 (2023).

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