2014 Research Fellow: Dr. Manish Patel

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Dr. Manish Patel – University of Minnesota

Dr. Manish Patel’s entire career has been focused on finding new treatments for lung cancer. After completion of residency at Northwestern University, he pursued an academic career in lung cancer research. He came to Minnesota in 2005 where he began research on the basic biology of lung cancers.

Upon completion of his fellowship in hematology and oncology at the University of Minnesota in 2010, he joined the faculty with an emphasis on lung cancer patient care and research. His goal is to translate findings in the laboratory to clinical trials for lung cancer to offer better treatments and ultimately a cure for lung cancer.

During his training, Dr. Patel developed an interest in studying live viruses as a therapy for lung cancer. Abnormalities in cancer cells can allow viruses to grow within them and kill them. Vesicular stomatitis virus, or VSV, is a virus that affects livestock, but is not pathogenic to humans. It has been further engineered to produce a key protein in our body’s defenses against viral infections, interferon-β. Production of interferon-β in a normal cell infected with VSV will rapidly inhibit spread of the virus, whereas cancer cells with defects in this pathway will allow viral replication. As a result, this virus efficiently kills cancer cells, while normal cells are not harmed.

In their preliminary experiments, vesicular stomatitis virus was highly effective against non-small cell lung cancer both in the culture dish and in mice with lung cancer. Some of the mice were cured of their lung cancer and were resistant to forming new tumors suggesting that VSV-IFNβ also resulted in an immune response against the tumors. Therefore, it is believed that that VSV-IFNβ will be an ideal therapy for lung cancer – resulting in both a direct cytotoxic effect specifically on the tumors and also an immune therapy resulting in long-term disease control.

The current focus of Dr. Patel’s lab team is to develop a strategy for bringing this therapy to clinical trials for lung cancer. The major barrier to virus therapy is that patients with cancer have an intact immune system and therefore, they must try to prevent the virus from circulating in the body. For metastatic lung cancer, this is a problem because it will limit the virus from reaching sites of metastatic tumors. Their approach is to use blood outgrowth endothelial cells (BOECs) as a carrier of the virus to the tumor. BOECs are unique cells derived from the blood, are easily cultured in the laboratory, and most importantly, circulate preferentially to sites of tumors. Dr. Patel and his team propose to use these cells as a “Trojan Horse” to carry VSV through the circulation hidden from the host immune system. In this way, they believe that BOECs will allow for effective virus therapy for metastatic lung cancer.

 


Final Report: Dr. Manish Patel

I want to thank A Breath of Hope for supporting our research. During the fellowship period, our research program has made significant strides. Though we did not complete our research aims as expected, we are proud that the results we have generated is likely to lead to an early phase clinical trial to test our oncolytic virus in patients with lung cancer.

During the fellowship period, we have learned quite a bit about the potential mechanisms by which VSV exerts its antitumor effect. Intriguingly, we have learned that VSV that expresses interferon (VSV-IFNb) when injected into a tumor, can stimulate the immune system to fight cancer throughout the body. We were able to publish these results in 2015 in a high-impact cancer journal. More importantly, the recent FDA approval of immune therapy for lung cancer has given us the opportunity to develop a novel clinical trial using VSV-IFNb with Nivolumab for patients with lung cancer. In mice, the combination of VSV-IFNb with anti-PD1 antibody (mouse version) works better than immune therapy by itself. Therefore, we feel that the combination may be quite effective in patients with lung cancer. We have already made initial discussions with the manufacturer of VSV-IFNb and have developed a clinical protocol to initiate a phase I study for patients with lung cancer. Therefore, we are gratified that our work in the lab will be translated to clinical testing in the very near future.

Secondly, we have learned about some of the molecular determinants of viral antitumor effects in lung cancer. Namely, our data suggest that the activity of interferon signaling pathways in lung cancer cells determine the ability of the virus to exert its effects. This finding has 2 important implications for future clinical research. First, we are now developing a molecular diagnostic test that may predict a group of patients that are likely to respond to viral therapy. We are now proposing to validate this test in upcoming clinical trials of VSV-IFNb-NIS in patients. Second, there are currently FDA approved drugs that can inhibit these pathways to make tumors that are resistant to viral therapy more sensitive. We are currently doing experiments in the laboratory to see if there is a good rationale for clinical testing of novel combination therapies.

Finally, the support that I have received during the fellowship period has been invaluable for continuing my career in lung cancer research. Importantly, we have now successfully competed for additional funding to continue our research. We have also been invited to apply for federal funding based on our results. Thank you for your generous support and I look forward to working with A Breath of Hope Lung Foundation in the future!

 


Progress Reports:  Dr. Manish Patel

March 2015 – Progress Report, Dr Patel: We are pleased to report progress on our work towards translation of VSV-IFNb to clinical application for patients with lung cancer.  We are continuing our work on utilizing blood outgrowth endothelial cells (BOECS) as a carrier of VSV-IFNb.  We are currently evaluating the overall survival of mice in a large cohort of mice and hope to have results to share very soon.  In the meantime, we have generated some data that are potentially very important with regards to future clinical application of VSV-IFNb.

First, we have learned that lung cancer cells with activated antiviral pathways might be resistant to VSV-IFN therapy.  This type of knowledge may be critically important when applying treatment to patients.  First and foremost, when we develop therapy clinically, this information gives us a starting point in identifying the correct patient who will benefit from this therapy and avoid using this therapy in patients who might not benefit as much.  More exciting is the knowledge that there is a drug, ruxolitinib, that can be used to overcome this resistance by inhibiting the antiviral pathway that leads to resistance.  Ruxolitinib is an FDA-approved oral drug that could be rationally combined with VSV-IFNb treatment for those patients who we think would be resistant to the virus by itself.

Secondly, we have now characterized the immune response to VSV-IFNb in mice with lung cancer.  We initially showed that VSV-IFNb treatment cured some mice of their lung cancer and they became resistant to rechallenge with lung cancer cells suggesting that mice developed ‘anti-tumor’ immunity.  We now have observed that direct injection of virus into tumors results in a reversal of the immune suppression common to lung cancer.  Importantly, this was seen not only in the tumors that were injected but also in tumors that were not directly injected.  The implications of this finding are that a direct tumor injection into one tumor could stimulate an immune response against tumors in other parts of the body.  We are excited about this result because of recent data suggesting that immune therapy for lung cancer can be quite effective for patients.  Moreover, this experiment could be directly translated to clinical testing in the near future as direct injection of VSV-IFNb is proving to be safe in humans already.

November 2014 – We are pleased to report progress on our project testing blood outgrowth endothelial cells as a carrier for vesicular stomatitis virus expressing interferon-b (VSV-IFNb) in treating non-small cell lung cancer.  Our first specific aim was to test the ability of BOECs carrying virus to deliver replicating virus to metastatic tumors in the lungs.  We are excited by our preliminary results.  Mice with metastatic lung cancer were injected by tail vein with BOECs alone, BOECs infected with VSV-IFNb, or VSV-IFNb without a cell carrier.  We repeated this treatment 2 weeks later and then sacrificed mice after treatment.  The mice treated with BOECs infected with VSV-IFNb did the best.  Lung weights after treatment were lower indicating reduced tumor burden in the lungs.  Moreover, the most replicating virus was detected in lungs of mice treated with infected BOECs, several logs greater than naked virus treatment. Mice treated with infected BOECs also had delayed development of anti-VSV neutralizing antibodies compared to naked virus after initial treatment.  By the end of the 2nd treatment, however, the anti-VSV neutralizing antibody titers were the same between naked and infected BOECs.  These data support our hypothesis that using BOECs will allow for systemic delivery of VSV and has therapeutic efficacy in mice with metastatic lung cancer.  In the coming months, we would like to determine if the virus is detectable in other areas other than the lungs, and how long viral replication remains active in the lung.  Moreover, we will confirm the efficacy results in a larger cohort of mice with an aim at improving their survival.