faculty lab
The Morris Lab
Radiation may augment the local and systemic anti-tumor immune response to cancer immunotherapies.
In the Morris Lab, we are focused on using preclinical and translational research approaches to study the mechanisms whereby radiation may impact the anti-tumor response to immunotherapies. Our primary objective is to determine whether and how radiation may optimally be employed to simultaneously modulate the tumor immune microenvironment and to increase the susceptibility of tumor cells to immune response. We seek to test these approaches in early phase clinical studies where they may be further refined with the ultimate aim of improving survival and achieving cures in patients with metastatic cancers.
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In Situ Tumor Vaccination
In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient’s own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an anti-tumor T cell response. Radiation therapy elicits an anti-tumor effect through induction of DNA damage in tumor cells, yet it has long been recognized that host immune capability and tumor immune susceptibility modulate the sensitivity of a tumor to radiation. The mechanisms by which local radiation may interact with the immune system include release of tumor-specific antigens, phenotypic changes in tumor cell expression of immune susceptibility markers and local eradication of suppressive immune cell lineages. By modulating tumor immune tolerance and functional immunogenicity at a targeted site, radiation may serve as a method of in situ tumor vaccination. Multiple preclinical studies demonstrate that random tumor-specific protein mutations are among the most immunogenic tumor antigens recognized by T cells. By rendering such antigens accessible to immune recognition, radiation may augment the local and systemic anti-tumor response to immunotherapy. If proven effective, such combinations might transform RT from a predominantly loco-regional treatment to a critical component of systemic therapy.
Relevant publications
Morris ZS, Guy EI, Francis DM, Gressett MM, Werner LR, Carmichael LL, Yang LL, Armstrong EA, Huang S, Navid JAF, Gillies SD, Hank JA, Rakhmilevich AL, Harari PM, Sondel PM. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Research. 2016 Jul 1;76(13):3929-41. PMID: 27197149.
Funding
- NIH Director’s Early Independence Award (DP5) 9/2017– 8/2022. Combining radiation and tumor-specific antibody therapies to elicit in situ vaccination. Role: Principal Investigator
- UWCCC Tumor Immunology/Cancer Immunotherapy Pilot Award 7/2017 – 6/2018. In situ vaccination to redress clinical challenges in the treatment of metastatic melanoma. Role: Principal Investigator (Morris, Kuo)
Effects of Radiation on Tumor Cell Immune Susceptibility
Prior studies have consistently demonstrated phenotypic upregulation of FAS and MHC-I following radiation therapy, and recent studies have suggested mechanisms whereby radiation may influence tumor expression of the checkpoint ligand, PD-L1. The time course, potentially shared underlying mechanisms and the possibility of a broader impact of radiation on expression of other phenotypic markers of tumor immune susceptibility remain to be clarified. Given the potential capacity of radiation to synergize with immunotherapies, it is vital to understand not only how radiation may affect tumor cell susceptibility to immune response but also to define the time course and mechanism of such effects.
Relevant publications
Werner LR, Kler JS, Gressett MM, Riegert M, Werner LK, Heinze CM, Kern JG, Abbariki M, Erbe AK, Patel RB, Sriramaneni RN, Harari PM, Morris ZS. Transcriptional-mediated effects of radiation on the expression of immune susceptibility markers in melanoma. Radiother Oncol. 2017 Sep 8. pii: S0167-8140(17)32526-4. PMID: 28893414.
Funding
- NIH Director’s Early Independence Award (DP5) 9/2017–8/2022. Combining radiation and tumor-specific antibody therapies to elicit in situ vaccination. Role: Principal Investigator
Development of new models and methods for testing novel combinations of radiation with immunotherapy
In a series of “next generation” studies, we are developing novel tumor models that will enable us to better test the efficacy of combinations of radiation with immunotherapies. At the same time, we are also exploring new methods for evaluating the mechanisms of interaction between these treatment modalities. In addition, we are actively exploring multiple unique approaches to optimizing this cooperative interaction through novel combinations of distinct radiotherapy modalities with diverse immunotherapies.
Funding
- Wisconsin Alumni Research Foundation 20/20 Award 10/2016–9/2018. Combining molecular targeted radiation with antitumor mAb and IL2 to create a potent in situ cancer vaccine. Role: Co-Principal Investigator (Sondel, Morris, Weichert, Bednarz, Otto)
- The Ride Scholars 1/2017–12/2017. Pilot investigation of novel combinations of molecular targeted immunotherapy with radiation. Role: Principal Investigator
- UWCCC Tumor Microenvironment Pilot Award 7/2017– 6/2018. Development of patient-derived xenografts in humanized mice. Role: Co-Principal Investigator (Kimple, Morris)
- RSNA Fellows Research Award 7/2017–6/2018. Utilization of Radiotherapy to Enhance the Efficacy of Systemic Dual Checkpoint Inhibition in Preclinical Metastatic Cancer Models. Role: Scientific Mentor for Ravi Patel
- UWCCC Tumor Immunology/Cancer Immunotherapy Pilot Award 7/2017–6/2018. In situ vaccination to redress clinical challenges in the treatment of metastatic melanoma. Role: Principal Investigator (Morris, Kuo)
- UW H&N SPORE Career Enhancement Program Award 7/2017–6/2018. Development of syngeneic murine head and neck squamous cell carcinoma tumor models for testing in situ tumor vaccination therapeutic approaches. Role: Principal Investigator
Early phase clinical trial development and correlative studies
As a physician-scientist, I help lead early phase clinical research efforts aimed at translating findings from our preclinical research to the clinic in order to improve treatment of cancer patients. We are currently advancing early phase clinical studies involving a variety of disease sites with the goal of improving clinical outcomes and cure rates for patients with cancer. Correlative biomarker studies and tissue samples from these clinical studies will be instrumental in allowing us to test the translational relevance of our preclinical findings, and this should enable us to refine our approaches to achieve greater clinical effect.