20 Aug Study Identifies CD70 as a Novel Glioblastoma Target
MedicalResearch.com Interview with:
Jianping Huang, MD, PhD
Director of Clinical Laboratory Operations
UF Brain Tumor Immunotherapy Program
Department of Neurosurgery, University of Florida
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Identification and validation of molecules that are involved in tumor progression and reduced survival in glioma patients is the starting point for developing active, safe and effective therapy. Unfortunately, very few target molecules have been identified for the deadly disease of glioma up until recently. Our studies have identified that the molecule CD70 is ectopically expressed on gliomas and involved in promoting glioma progression. Our research shows that CD70 leads to a “double jeopardy” scenario in Glioblastoma (GBM) patients by promoting tumor aggressiveness and inhibiting our immune response to cancer. These results provide a strong scientific rationale to target CD70 using state-of-the-art therapeutic approaches, such as chimeric antigen receptor (CAR) T cell therapy.
MedicalResearch.com: Can you explain what CD70 is and how it affects tumor development?
Response: Normally, CD70 is tightly regulated and expressed on some immune cells that are highly activated. However, CD70 is also found to be expressed on the surface of various malignancies, including gliomas. The abnormal expression of CD70 on tumor cells remolds the tumor landscape and increases the tumor’s ability to migrate and grow, while this expression suppresses the body’s normal immune response, therefore allowing Glioblastoma tumors to progress.
MedicalResearch.com: Which of the results would you consider to be the most significant, and why?
Response: There is a lack of accessible therapeutic target in GBM. Characterizing the involvement of CD70 in both tumor progression and tumor microenvironment regulation has led us to identifying CD70 as a novel glioblastoma target. Furthermore, by using CD70 CAR-T cells, we have demonstrated a viable therapeutic approach toward CD70. We think this finding shows the vast potential of immunotherapy and hold promise for GBM cancer treatment.
MedicalResearch.com: Generally speaking, can you explain why finding tumor-produced factors associated with immunosuppression is so critical to the development of successful immunotherapeutic interventions?
Response: The immune system could effectively recognize “non-self” invaders such as neoplasms if it functions properly. However, tumor cells can induce immunosuppression by secreting certain factors that inhibit the immune system and contribute to immune dysfunction, thus helping them evade immune detection and escape immune response. If we identify more tumor-produced factors, we can potentially develop ways to combat immunosuppression and reactivate the immune system, thereby reversing tumor progression.
MedicalResearch.com: What happens next with this line of research, and when? Specifically, can you elaborate on the process of testing CD70-specific CAR T cell therapy?
Response: CD70 CAR T therapy shows potent antitumor response in our preclinical studies. Ultimately, our goal is to translate this therapy to glioma patients. As a first step towards achieving this goal, we would like to investigate combining CAR T therapy with current treatment methodology.
For example, our current research shows that radiation has the potential to guide more CAR T cells infiltration into the tumor site. In mouse models, our preliminary data show that local radiation improved the homing and the antitumor activity in CD70 CAR T cells. These results allow us to combine radiotherapy with CAR-T therapy.
MedicalResearch.com: What are your “big picture” thoughts on how these findings offer “great hope for patients with CD70-positive Glioblastomasin the near future.”
Response: Cancer immunotherapy has represented one of the most promising new treatment strategies for glioma patients. However, very few tumor specific targets have been discovered. Thus, identifying clinically useful targets for immunotherapeutic approaches is critical. Our preclinical studies show that CD70 is a viable target, and CD70 CAR-T therapy can induce robust antitumor response as it eliminates two key driving forces of tumorigenesis. In addition, our results illustrate that CD70 is not only highly expressed by primary tumors, but also in recurrent tumors. Therefore, CD70 CAR-T therapy is potentially ideal for patients with recurrent GBM. Moreover, our preliminary research has shown that radiation enhances CD70 expression on gliomas, potentially allowing us to combine standard care with CD70 CAR T therapy to enhance antitumor efficacy. We are working towards translating our findings into the clinic in the near future.
MedicalResearch.com: What, if any, caveats or study limitations should I be aware of?
Response: Our studies indicate that about 35% of newly diagnosed GBM patients (more in recurrent GBM patients) are carrying CD70 on their tumors. Within these CD70 positive patients, not all individual tumor cell expresses CD70 (on average, 78% of tumor cells are CD70 positive). This is the hallmark of tumor heterogeneity in glioma. Thus, CD70 CAR T cells are unable to kill tumors in CD70 negative patients. This is also the biggest caveat for all cancer therapy approaches — demonstrating efficacy in subsets of cancer patients. We are currently working hard to identify more cancer targets in the hope of offering combination therapies to treat glioma patients.
MedicalResearch.com: If you were at a dinner party with your non-scientist friends, how would you explain these findings and the significance to them in a way that they could understand and appreciate?
Response: Glioblastoma is a deadly brain tumor, the average/media life expectancy is less than 15 months. Over the past 3 decades, treatment of glioblastoma has not significantly improved. Cancer immunotherapy represents one of the most promising new treatment strategies for cancer patients.
One of the new approaches, called CAR-T therapy, turns ordinary T cells of cancer patients into tumor-killing T cells. By giving these CAR T cells to patients, the army of T cells can locate the tumor and destroy tumor cells. Currently, only very few CARs in clinical trials have been developed for glioblastoma.
Our preclinical studies have shown that CD70 specific CAR T cells can kill tumor cells derived from patients, and that tumor-bearing animals were cured or survived longer when treated with CD70 CAR T cells.
MedicalResearch.com: Is there anything else you would like to add?
Response: I would like to thank our leadership, Drs. William Friedman and Duane A. Mitchell, as well as everyone here at the UF Brain Tumor Immunotherapy Program; our collaborators, Dr. Zhiguo Lin from Department of Neurosurgery, Harbin Medical University, China; and Drs. Qiong J. Wang and James C. Yang from NCI for their contributions and support, we can’t achieve these without them.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Tumor associated CD70 expression is involved in promoting tumor migration and macrophage infiltration in GBM.
Ge H1, Mu L1, Jin L2,1, Yang C2, Chang YE2, Long Y2,1, DeLeon G2, Deleyrolle L2, Mitchell DA2, Kubilis PS2, Lu D1, Qi J3, Gu Y3, Lin Z1, Huang J2.
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