Immune Checkpoint Modulation

Immune Checkpoint Assay

Schematic & images adapted from reference (1) Jenkins et al.

Despite the success of immune checkpoint blockade (ICB) therapies in recent years, they are limited to a minority of patients due to innate (primary) resistance. Combination therapy that uses dual ICB, anti-PD-1 and anti-CTLA4 has shown promising results in advanced melanoma as compared to either monotherapy. As the number of combination therapies is ever increasing, there is a need for an ICB assay that can accurately predict the efficacy of these therapies in the preclinical and clinical settings in a timely manner. Murine-derived/patient-derived organotypic tumor spheroids (MDOTS/PDOTS) developed by Jenkins et al in AIM 3D cell culture devices address this need (see reference (1)). MDOTS/PDOTS isolated from mouse and patient tumors retain the autologous immune cells and matrixes which are critical for the ICB response. The preserved tumor microenvironment ensures that the tumor-immune and cell-matrix interactions are not compromised in this ex vivo assay. MDOTS/PDOTS not only recapitulate the in vivo immune response (as shown below), but also yield the results within a week which can help accelerate the drug discovery process.

Immune Checkpoint Validation

Immune Checkpoint Validation

MDOTS cultured in AIM chips capture the in vivo responses of PD-1 sensitive MC38 and PD-1 resistant B16F10 under PD-1 treatment. The MC38 MDOTS respond to PD-1 treatment in a dose dependent manner while the B16F10 MDOTS do not respond to the PD-1 treatment at all dosages.

Data & images adapted from reference (1) Jenkins et al.

Immune Checkpoint Drug Discovery

Immune Checkpoint Drug Discovery

MDOTS cultured in AIM chips capture the in vivo responses of PD-1 sensitive MC38 and PD-1 resistant B16F10 under PD-1 treatment. The MC38 MDOTS respond to PD-1 treatment in a dose dependent manner while the B16F10 MDOTS do not respond to the PD-1 treatment at all dosages.

Data & images adapted from reference (1) Jenkins et al.

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Please refer to reference (4) by Aref et al for details on conducting the immune checkpoint assay.

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References

  1. *Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Jenkins RW, Aref AR, Lizotte PH, Ivanova E, Stinson S, Zhou CW, … Barbie DA. Cancer Discov. 2017 Nov 3. pii: CD-17-0833. doi: 10.1158/2159-8290.CD-17-0833.
  2. *CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation. Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, … Wong KK. Cancer Discov. 2017 Nov 3. pii: CD-17-0915. doi: 10.1158/2159-8290.CD-17-0915.​
  3. *Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Cañadas I, Thummalapalli R, Kim JW, Kitajima S, Jenkins RW, Christensen CL… Barbie DA. Nature Medicine 23 July 2018 doi.org/10.1038/s41591-018-0116-5
  4. *3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Aref AR,  Campisi M, Ivanova E, Portell A, Larios D, Piel BP… Jenkins RW. Lab on a Chip, 5 Sep 2018, DOI: 10.1039/C8LC00322J
  5. *Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Kitajima S, Ivanova E, Guo S, Yoshida R, Campisi M… Barbie DA. Cancer Discov. Epub 8 Oct 2018 DOI: 10.1158/2159-8290.CD-18-0689
  6. *BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non–Small Cell Lung Cancer. Adeegbe DO,  Liu SW, Hattersley MM, Bowden M, ZhouCW, Li S… Wong KK. Cancer Immunol Res; 6(10); 1234–45. Epub 7 Aug 2018 DOI: 10.1158/2326-6066.CIR-18-0077
  7. *Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG,  Jenkins RW… Hacohen N. Cell  vol 175, issue 4, P998-1013.E20, November 01, 2018. https://doi.org/10.1016/j.cell.2018.10.038
  8. *Molecular recalibration of PD-1+ antigen-specific T cells from blood and liver.  Otano I, Escors D, Schurich A, Singh H, Robertson F, Davidson BR…  Maini MK. Molecular Therapy (7 Nov 2018), doi: 10.1016/j.ymthe.2018.08.013.
  9. *RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Wang W, Marinis JM, Beal AM, Savadkar S, Wu Y, Khan M… Miller G. Cancer Cell 34, 757–774, November 12, 2018. https://doi.org/10.1016/j.ccell.2018.10.006

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