Moderna mRNA based cancer vaccine for Non Muscle Invasive Bladder Cancers (NMIBC) Phase 2 seems to have progressed well and GlobaLData which is data and analytic provider posted an article on August 30, stating Moderna mRNA-4359 + Keytruda combination for NMIBC has a 72% phase transition success rate (PTSR) indicating bench mark for progressing to Phase 3. Below shows the history of FDA approving phase transitions for oncology drugs between 2011-2020.
Phase 1 to 2 1628 Phase POS 48.8%
Phase 2 to 3 1732 Phase POS 24.6%
Phase 3 to NDA/BLA 496 Phase POS 47.7%
NDA/BLA to Approval 324 Phase POS 92.0%
Phase transition success rate (PTSR) is only 24.6% for oncology related treatment. So, 72% PTSR indicates Moderna-4359 + Keytruda combination must have had very good result for NMIB. It is not certain whether and when Moderna and Merck want to start Phase 3 clinical trial for Moderna-4359 mRNA based vaccine with combination of Keytruda PD-1 check point inhibitor immunotherapy but had they decided to go ahead with Phase 3, it is highly likely FDA will approve Phase 3 to be started.
Note that I do not now how data and analytic provider gained the result of Phase 2 study, I am very curious what kind of antigens Moderna had chosen for NIMBC. Also, we want to know the detail result of Phase 2.
Phase I clinical trial of mRNA based cancer vaccine for pancreas cancer
The result of Phase I clinical trial of mRNA based cancer vaccine for pancreas cancer was published on May 10, 2023 in Nature.
PDAC (Pancreas Duct Adeno Carcinoma) is the the third leading cause of cancer death in the US. The survival rate of 12% has remained stagnant for 60 years. Surgery is the only curative treatment, yet 90% of patients have disease recurrence at median 7-9 months. Multiagent chemotherapy delay recurrence but the 5 years overall survival is only 8-10%. PDAC us insensitive to immunotherapy with less than 5% response rate. However, recent observations have shown that most PDACs in fact harbor more neoantigens. This has shown a possibility that vaccine against those neoantigens may work for PDAC. Subsequently, MSK ( Memorial Sloan Kettering Cancer Center) initiated Phase 1 clinical trial, which was funded by NIH( National Institute of Health) and it result was published in Nature.
The project was led by Dr. Balachandran of MSK with collaboration with Genentech, a member of the Roche Group, and BioNTech. BioNTech provided mRNA technology, which was used for Pfizer mRNA based Covid-19 vaccine, and Genentech provided PD-L1 checkpoint inhibitor immunotherapy drug Tecentriq(R) (Atezolizumab). MSK used its own IMPACT (Integrated Profiling of Actionable Cancer Targets) to identify specific gene mutation from patients pancreas cancer tissue.
The clinical trial
After surgery to remove PDAC, the team sent tumor samples from 19 people to partners at BioNTech. BioNTech performed gene sequencing on the tumors to find proteins that might trigger an immune response. They then used that information to create a personalized mRNA vaccine for each patient. Each vaccine targeted up to 20 neoantigens. Customized vaccines were successfully created for 18 of the 19 study participants. The process, from surgery to delivery of the first dose of the vaccine, took an average of about nine weeks. All patients received immunotherapy drug Tecentriq before vaccination. Tecentriq prevents cancer cells from suppressing the immune system. The vaccine was then given in nine doses over several months. After the first eight doses, study participants also started standard chemotherapy drugs for PDAC, followed by a ninth booster dose.
Sixteen volunteers stayed healthy enough to receive at least some of the vaccine doses. In half these patients, the vaccines activated powerful immune cells, called T cells, that could recognize the pancreatic cancer specific to the patient. To track the T cells made after vaccination, the research team developed a novel computational strategy with the lab of Dr. Benjamin Greenbaum at MSKCC. Their analysis showed that T cells that recognized the neoantigens were not found in the blood before vaccination. Among the eight patients with strong immune responses, half had T cells target more than one vaccine neoantigen.
By a year and a half after treatment, the cancer had not returned in any of the people who had a strong T cell response to the vaccine (50%). In contrast, among those whose immune systems didn’t respond to the vaccine, the cancer recurred within an average of just over a year (50%). In one patient with a strong response, T cells produced by the vaccine even appeared to eliminate a small tumor that had spread to the liver. These results suggest that the T cells activated by the vaccines kept the pancreatic cancers in check.
They do not not know 50% of patients responded well to the vaccine but 50% did not.
It took only 9 weeks from the surgery, taking patients' tissue sample of pancreas cancer, MSK to identify cancer related gene mutation, BioNTech to produce mRNA based vaccine for about 20 patient specific neoantigens, and till first injection of the vaccine.
A larger clinical trial at global level is in the plan according to the article. Below are the link to related article and studies.
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.
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.
First, I apologize ahead that the information I provide is all from my superficial knowledge and there may be mistake. So, this is just for awareness.
Amino acids - there are 21 different amino acids, of which 11 are made by our body and 10 must be obtained by consuming food. A protein is in general a long chain of amino acids. The long chain of amino acids folds and make a 3 dimensional figure. Peptide is a small chain of amino acids, It can be a part of protein. Antigen is general protein MERCK website
Many tumor cells produce antigens, which may be released in the bloodstream or remain on the cell surface. Any molecule capable of being recognized by the immune system is considered an antigen. Antigens have been identified in most of the human cancers, A key role of the immune system is detection of these antigens to permit subsequent targeting for eradication.
Tumor-associated antigens (TAAs) are relatively restricted to tumor cells. Tumor-specific antigens (TSAs) are unique to tumor cells. TSAs are also termed neoantigens.
TSAs and TAAs typically are portions of intracellular molecules expressed on the cell surface as part of the major histocompatibility complex (MCH).
Wikipedia says an epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope.
Our immune system in general does not respond TAA. For example, NECTIC-4 is antigen which is expressed in high number on the cell membrane of bladder cancer cells. Because normal cells also express NECTIN-4 antigens, eg. healthy epidermal cells of skin express NECTIN-4, our immune cells do not respond to NECTIN-4 antigen expressed by bladder cancer cells. NECTIN-4 is an example of Tumor-associated antigens (TAAs). So, NECTIN-4 is not a good target antigen for cancer vaccine. Instead, PADCEV utilizes NECTIN-4 antigen as target for antibody-drug conjugate to arrive to bladder cancer cells which express NECTIN-f and deliver very toxic chemotherapy drug to kill cancer cells. It is noted that a common side effect of PADCEV-4 is itchiness of skin because PADCEV also binds to NECTIN-4 which is also expressed by normal epidermal cells of skin.
Bladder cancer vaccine - S-588410 by Shionogi Pharma in Japan.
S-588410 is a cancer vaccine which contains five different epitope peptides (a part of antigens) found on testis cancer. five different peptides are from antigens DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC which are also highly expressed on cancer cells of various solid tumors, including melanoma, lung, esophageal cancer, bladder cancer, etc. Those five antigens are tumor-specific antigens (TSAs) are unique to tumor cells.
Instead of Moderna mRNA based cancer vaccine, which contains lipid encapsulated tumor causing genes which are found in cancer patient and let patient's cells to produce antigens, S-588420 or a cocktail of five different epitope peptides are directly injected to patients subcutaneously as an emulsion. Our immune system sees epitope peptides as pathogen and respond by stimulating cytotoxic T-lymphocytes (CTL) and producing many Killer T-cells against cancer cells which express any one of five different epitope peptides.
Phase 3 clinical trial of S-588410 for Esophagus cancers was conducted in Japan. Shionogi reported in July, 2021 that Phase 3 trial of S-588410 did not improve recurrence free survival duration compared to placebo. But, S-58841had stimulated cytotoxic T-lymphocytes (CTL) well. Main side effects were limited to the area of skin where S-588410 was injected.
The result of Phase 3 clinical trail of S-588410 is a bit disappointing because S-588410 alone may not work for bladder cancers either.
There is another cancer vaccine Phase I/I clinical trial going on in the UK. The trial (Druance) is for bladder cancer based upon Duralumab and the vaccine S-588410. The clinical trial is being backed up by Shionogi Pharmaceutical Co ( $4B annual revenue ) in Japan and AstraZeneca ($44B annual revenue) in England. This is probably why the phase II clinical trial is being conducted at University College London (UCL) CRUK & UCL Cancer Trials Centre
Duralumab is PD-L1 checkpoint inhibitor immunotherapy drug, which his similar other PD-L1 checkpoint inhibitor immunotherapy drugs by Tecentriq by Roche and Avelumab by Pfizer, The idea is that S-588410 is invoking immune responses but cancers are evading from immune responses. So, disabling cancer cells evading from immune responses, it should enable immune cells to kill cancer cells. Let's hope for a good result from S-588410 + Duralumab as vaccine for bladder cancer.