In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors
Danny N. Khalil, … , Jedd D. Wolchok, Taha Merghoub
Danny N. Khalil, … , Jedd D. Wolchok, Taha Merghoub
Published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3435-3447. https://doi.org/10.1172/JCI128562.
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Research Article Oncology

In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Abstract

Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti–PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues.

Authors

Danny N. Khalil, Nathan Suek, Luis Felipe Campesato, Sadna Budhu, David Redmond, Robert M. Samstein, Chirag Krishna, Katherine S. Panageas, Marinela Capanu, Sean Houghton, Daniel Hirschhorn, Roberta Zappasodi, Rachel Giese, Billel Gasmi, Michael Schneider, Aditi Gupta, James J. Harding, John Alec Moral, Vinod P. Balachandran, Jedd D. Wolchok, Taha Merghoub

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Figure 1

Agents that promote phagocytosis and APC activation, but not direct tumor cell lysis, control local and distant tumors.

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Agents that promote phagocytosis and APC activation, but not direct tumo...
(A) Bone marrow–derived myeloid cells were treated with MPL or vehicle for 16 hours and incubated with FITC-labeled latex beads. Flow cytometry was performed to determine the fraction of CD11chi cells that phagocytosed FITC-labeled beads and the median fluorescence intensity (MFI) of CD86 expression (n = 3 – 5/group). (B) C57BL/6 mice were implanted intradermally with 5 × 105 B16F10 cells. On day 8, FITC-labeled latex beads were coinjected intratumorally with vehicle, MPL, or anti-CD40. Twenty-four hours later, the CD11chi cell population was analyzed in tumors (left) for phagocytosis (n = 5/group) and in DLNs (right) for CD86 expression (n = 4/group). (C) Treatment schedule: intratumoral biweekly treatments, with or without intraperitoneal anti–PD-1, were started once bilateral tumors were established; treatment was continued for 4 weeks. (D) Individual growth curves of treated and distant tumors in animals treated with MPL and anti-CD40 (n = 10/group). (E) Average tumor growth curves comparing MPL and anti-CD40 with constituent monotherapies (n = 10/group). (F) Viability of B16F10 cells treated in vitro with MPL, anti-CD40, or gemcitabine for 72 hours. (G) Growth of treated and distant tumors upon addition of anti–PD-1 (n = 10/group). *P ≤ 0.0, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by unpaired, 2-tailed Student’s t test.