I would like to wrap up about the development of cancer vaccine in general by reviewing voices of senior management of pharmaceutical companies. The summary of discussion among the executives on cancer vaccine at JP Morgan's investors' conference on healthcare business was published by FIERCE Biotech website on January 25, 2023.
"Bristol Myers CMO, others still skeptical about cancer vaccines as BioNTech, Moderna march ahead with I-O partners".
Note CMO stands for chief medical officer, and I-O stands for Immune- Oncology, i.e. immunotherapy. BioNTech is a German biotechnology company, who developed mRNA based drug technology similar to Moderna and partnered with Pfizer to develop mRNA based COVID-19 vaccine which was marketed as Pfizer mRNA based Covid-19 vaccine. Moderna mRNA based COVID-19 and Pfizer/BioNtech mRNA base COVID-19 are very similar as product also in technology used.
1. The first major cancer vaccine development was done on prostate cancers. Prostvac vaccine is comprised of engineeringly designed molecule of PSA and three T-cells costimulatory molecules -B7, LFA-3, and ICAM. Prostvac was developed by NCI and its technology was transferred to a pharmaceutical company. Phase 2 clinical trail produced promising result but Phase 3 showed no improvement by Prostvac compared to placebo, so a half billion dollar Danish vaccine manufacturer Bavarian Nordic decided to terminate Phase 3 clinical trial in 2017. So Bavarian Nordic decided to try combining Prostvac and Bristol Myer Squibb immunotherapy drug Nivolumab (Opdivo). The phase I/II clinical trial NCT02933255 is still going on. In 2021, a study paper says he combination of Neoadjuvant Prostvac and nivolumab was associated with increased immune cell infiltration in a cohort of early prostate cancer patients. A broader examination of the TIME and the role immune cells undertake to control tumor growth is on-going." Note that it is known that prostate cancers do not respond well to immunotherapy as well as to bladder cancers. So, Prostvac and immunotherapy combination is a creative way to induce immune responses by Prostvac and have immunotherapy to kill cancer cells which evade from immune responses.
This video explain how Prostvac was designed and mechanism of action. The video is 8 years old.
Study on Prostvac and immunotherapy combination
2. BioNtech mRNA based vaccine technology platform Fixvac. Shots were developed with the platform include fixed combinations of antigens that are frequently expressed and shared across patients of a cancer type; very similar approach as Moderna mRNA based cancer vaccine. A large pharmaceutical company has Libtayo, which is PD-1 immune check point inhibitor immunotherapy drug similar to Pembrolizumab (Keytruda) by Merck. So, BioNtech and Regeneron have a joint project to develop cancer vaccine for PD-1 progressed Melanoma and etc. Cancer vaccines for Regeneron Libtayo with BioNtech mRNA based vaccine Fixvac and MERK Keytruda with Moderna mRNA based vaccines are very similar in technology. Main difference is in the use of antigens. Moderna approach is to find antigens from each patient so very customized, where BioNtech uses antigens common to patients with a particular cancer type.
Roche has also partnered with BioNTech but on the German biotech’s individualized mRNA vaccine platform, iNeST. Roches has Tecentriq PD-L1 immune checkpoint inhibitor immunotherapy. This combination treatment is for pancreatic cancers.
3. Convenience. Though cancer vaccine without using immunotherapy drugs which have been given intravenously is simple but efficacy so far seems to be less effective.
4. Immunotherapy costs around $100K year list price, so cancer vaccine which requires immunotherapy will limit the use of cancer vaccines only for specific circumstances. Also, immunotherapy causes various systemic side effects. These limitation may limit the use of cancer vaccine to only patients with very high risk of recurrences such as for prevention of recurrence of metastatic cancers.
5. When and for what situation should cancer vaccine be used?
Genentech's Mellman said. “I can imagine a situation where [a cancer vaccine] then becomes an adjunct to anything that you do. You vaccinate somebody to prevent the tumor from coming back. I can think of several applications as adjuvant treatment by cancer vaccine for bladder cancers.
a) After radical cystectomy. Right now , most patients who had radical cystectomy are put on surveillance by regular CT scans. But, if cancer vaccine detect and kill cancers in its infancy, it is more effective than after cancers establish in some organ and discovered after it has grown to be a certain size which can be detected by CT scan.
b) After chemotherapy or immunotherapy are completed for metastatic bladder cancers.
c) After BCG treatment is completed.
Mellman also talked about the use of cancer vaccine even before cancer is formed. He said “I think with the advances that are being made in looking at [circulating tumor DNA] and deep sequencing of them, we may reach a point where we’ll be able to detect what neoantigens or conserved antigens or whatever are actually being made long before there’s a discernible radiologic tumor
In summary, at this point, cancer vaccine is to introduce cancer specific antigens into our body directly or indirectly and depends on our immune system to responds to those antigens in sufficient strength which is enough to kill cancer cells which are expressing those antigens. But is seems that cancer vaccines are not enough to have viable efficacy, so immunotherapy drugs are used to enhance the efficacy by inhibiting cancer cells from evading the immune responses.. The need to use immunotherapy as combination is makes cancer vaccines a bit cost inhibitive and limit the application at present. But, the patent of Keytruda expires in 2018. Then, the cancer vaccine with combination of immunotherapy will be less cost inhibitive. Also, other technology advances, i.e. sharp declining in cost in analyzing DNA and etc. should make cancer vaccine to be accessible to broader applications in bladder cancers.