At the 2016 annual meeting of the American Association for Cancer Research (AACR) one topic that attracted a lot of attention and debate was the use of mouse models to guide cancer immunotherapy drug development strategy.
Bernard A. Fox, PhD (pictured above) is Chief, Laboratory of Molecular and Tumor Immunology and holds the Harder Family Chair for Cancer Research at the Earle A. Chiles Research Institute at Providence Cancer Center. He’s also President and CEO of UbiVac.
You can follow him on Twitter at @BernardAFox.
One of the emerging challenges in developing new cancer immunotherapies, and in particular combination strategies, is that mouse models don’t always predict what will happen in humans.
We’ve cured cancer in mice many times over, but it’s tougher in humans because there’s more complexity. There is an onging debate in the cancer immunotherapy field as to whether we need more effective mouse models.
The Society for Immunotherapy of Cancer (SITC) have a whole day workshop devoted to this topic at their 2016 annual meeting in November: Workshop on Challenges, Insights, and Future Directions for Mouse and Humanized Models in Cancer Immunology and Immunotherapy.
At AACR 2016, research from Dr Fox’s laboratory was presented by David J. Messenheimer, PhD (Abstract 4361: Timing of PD-1 blockade is critical to successful synergy with OX40 costimulation in preclinical mammary tumor models.) They showed in mouse model, giving an anti-OX40 agonist at the same time as a PD-L1 checkpoint inhibitor led to an attenuation of response, suggesting that timing and sequencing of checkpoint modulators may be critical in future combination strategies.
In this episode, you’ll hear Dr Fox discuss the data and its implications.
You’ll also hear from a clinical scientist whose company didn’t see the same results in their mouse models when an anti-OX40 and PD-L1 monoclonal antibody were combined. Their clinical trial strategy is to give the two molecules at the same time.
Ina Rhee, MD PhD is a Medical Director at Genentech and was co-author of a presentation at AACR 2016 on the first-in-human clinical data for a novel anti-OX40 monoclonal antibody (Abstract CT097: A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumours.)
Dr Rhee discusses the OX40 monotherapy data presented at AACR, the rationale for combining an OX40 agonist with a PD-L1 checkpoint inhibitor, and some of the key challenges faced in R&D as compounds move from the preclinical to clinical setting.
The first clinical data for this combination is expected at ASCO 2016 (Abstract 101: A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumours.“)
We await the clinical data to see whether Dr Fox is right based on the mouse model data from his laboratory or whether Genentech need to revise their combination strategy.
This controversy over conflicting mouse model results highlights the challenges faced by the cancer immunotherapy field in moving novel combination strategies forward and designing clinical trials.
In addition to combinations with checkpoint modulators, there is a lot of interest in combining chemotherapy with checkpoints. At AACR 2016, we asked a leading expert about the rationale for this combination strategy.
Professor Melief discusses research that shows chemotherapy acts on the immune system; chemotherapy is immunotherapy.
This could result in a paradigm shift in how chemo is used, if the effect it has on the immune system can be generated with lower doses than are currently used to kill cancer cells.
Instead of using the maximum tolerated dose (MTD), with all the toxicities that accompany it, a lower minimum effective dose may be sufficient to generate an immune response. This would be a big shift in how we think about using chemo in future combination trials.
We look forward to learning more at forthcoming medical meetings on the effectiveness of combining chemo with PD-1/PD-L1 checkpoint inhibitors.
Update on August 28th 2017 by @maverickny
There’s now an update to this story on Biotech Strategy Blog with the publication of two key pieces of research from Dr Fox and Khlief’s labs. This in-depth article includes a full interview with Dr Fox as well as some additional commentary from Dr Ira Mellman (Genentech), following the company’s decision in July 2017 to abandon development of the OX40 molecule discussed by Dr Rhee in this episode.
You can get a glimpse of Dr Fox’s interview below:
Below are links to some of the scientific papers mentioned in this episode, and others that may be of interest:
Kroemer G, Galluzzi L, Kepp O, & Zitvogel L (2013). Immunogenic cell death in cancer therapy. Annual Review of Immunology, 31, 51–72 PMID: 23157435
Pfirschke C, Engblom C, Rickelt S, Cortez-Retamozo V, Garris C, Pucci F, Yamazaki T, Poirier-Colame V, Newton A, Redouane Y, Lin YJ, Wojtkiewicz G, Iwamoto Y, Mino-Kenudson M, Huynh TG, Hynes RO, Freeman GJ, Kroemer G, Zitvogel L, Weissleder R, & Pittet MJ (2016). Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity, 44 (2), 343–54 PMID: 26872698
Welters MJ, van der Sluis TC, van Meir H, Loof NM, van Ham VJ, van Duikeren S, Santegoets SJ, Arens R, de Kam ML, Cohen AF, van Poelgeest MI, Kenter GG, Kroep JR, Burggraaf J, Melief CJ, & van der Burg SH (2016). Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Science Translational Medicine, 8 (334) PMID: 27075626
Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, Walker J, Gonzalez I, Meeuwsen T, Fox BA, Moudgil T, Miller W, Haley D, Coffey T, Fisher B, Delanty-Miller L, Rymarchyk N, Kelly T, Crocenzi T, Bernstein E, Sanborn R, Urba WJ, & Weinberg AD (2013). OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Research, 73 (24), 7189–98 PMID: 24177180
Feng Z, Puri S, Moudgil T, Wood W, Hoyt CC, Wang C, Urba WJ, Curti BD, Bifulco CB, & Fox BA (2015). Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma. Journal for Immunotherapy of Cancer, 3 PMID: 26500776
Feng Z, Jensen SM, Messenheimer DJ, Farhad M, Neuberger M, Bifulco CB, & Fox BA (2016). Multispectral Imaging of T and B Cells in Murine Spleen and Tumor. Journal of Immunology PMID: 26994219
Moran AE, Kovacsovics-Bankowski M, & Weinberg AD (2013). The TNFRs OX40, 4–1BB, and CD40 as targets for cancer immunotherapy. Current Opinion in Immunology, 25 (2), 230–7 PMID: 23414607
Institute of Medicine Workshop on Feb 29, 2016: Policy Issues in the Clinical Development and Use of Immunotherapy for Cancer
As mentioned by Dr Fox on the podcast, copies of presentations and videos are available on the Institute of Medicine website. Dr Fox spoke in the session covering Challenges with preclinical models for immunotherapy, you can watch his talk below:
This podcast episode was produced thanks to sponsorship from Genentech.
Please note we included excerpts from the interview with Dr Rhee, not because she works for Genentech, but because she was a co-author on a presentation presented at AACR. We made an independent editorial decision to include this on the podcast.
All the interviews were originally published on Biotech Strategy Blog (subscription required).
The music in this podcast episode is by electric violinist and composer David Schulman from his album Quiet Life Motel.
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