cancer Vaccine

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". 

www.fiercebiotech.com/biotech/bristol-myers-cmo-still-skeptical-about-cancer-vaccine-biontech-moderna-march-ahead-i-o

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 
jitc.bmj.com/content/9/Suppl_2/A450

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.  

Background

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).

Epitope
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.   

Recently, several investment news media reported Moderna's cancer vaccine for Melanoma being closed to be approved by the FDA.  Below is from Yahoo Finance reporting the recent progress Moderna made on its mRNA based cancer vaccine + Keytruda immunotherapy for advanced Melanoma.  I will try to decipher the current status of cancer vaccines using  the Moderna’ cancer vaccine as an example

.finance.yahoo.com/news/moderna-merck-announce-mrna-4157-210500806.html

Moderna is a pharmaceutical company who specializes in mRNA technology.  The company was founded in 2010.  The company was not making money until their mRNA based vaccine for COVID-19 was approved by FDA along with Pfizer/Biotech mRNA based vaccine.  So, the Moderna cancer vaccine uses the knowhow they gained for COVD-19 vaccine.    

1.  Identify which antigens (proteins) of cancer cells will invoke a strong immune response.
2.  Encapsulate DNA or mRNA for the specific antigen or antigens in a nano size lipid.
3.  Inject into an arm many lipids or many viruses  which contain DNA/mNRA of antigens of cancer
4.  Lipids go inside cells of our body.
5.  When lipids reach  the cytoplasm area of a cell, it releases mNRA.
6.  Enzyme called RIbosome reads mRNA and produces antigens.
7. When antigens go outside of the cell,  our immune system recognizes antigens as pathogens and produces antibodies and T-cells.  
8.  And antibodies and T-cells circulate through blood vessels.
9. When a cancer cell arises which expresses the antigens which T-cells recognize, T-cells kill the cancer cell. 

What is unique about the Moderna  cancer vaccine is that antigens are obtained  from cancer of a patient. So, they call the Moderna cancer vaccine “personalized cancer vaccine”.   Also, because Moderna is an expert in mRNA based vaccine, Moderna claims that once they identify which antigens the vaccine should target, the personalized cancer vaccine can be made within a few months,

As any cancer drug development is financially risky,  Moderna has chosen Merck as a partner for its cancer vaccine development.    Merck invested $250 million worth shares  in Moderna for its cancer vaccine development and Merk and Moderna split revenue from the sale of Cancer vaccine for Melanoma.   The first cancer vaccine Moderna developed was the combination of Keytruda immunotherapy drug and Moderna cancer vaccine for Melanoma.  This approach makes sense as even if the vaccine invokes immune responses against specific antigens of cancer cells, we know that cancer cells can evade T-cells by expressing PD-L1 immune checkpoint on cancer cells.  Keytruda (PD-1 immune checkpoint inhibitor) lets T-cells ignore PD-1 immune checkpoint and go ahead to kill cancer cells regardless of PD-L1 being expressed on cancer cells.  

Phase II of the clinical trial which compared Moderna Cancer Vaccine +  Keytruda vs Keytruda alone showed 44% improvement in efficacy.   The vaccine is given in nine doses every 21 days , in combination with one dose of Keytruda every 21 days up to 18 times.
The participants were patients with stage III or IV resectable cutaneous melanoma, which had metastasized to a lymph node, who were considered to have high risk of recurrence. They were eligible if following complete resection, they had no loco-regional relapse or distant metastasis and no clinical evidence of brain metastases.   Note that vaccine for bladder cancer is in a pipe lines for mRNA based cancer vaccine development by Moderna.

It is noted that a cancer vaccine is not to prevent cancer from arising but rather killing as cancer as soon as the cancer arises.   This is in contrast to other vaccines including the vaccine for COVID-19.   The vaccine for COVID-19 first prevents us from being infected with the virus by using antibodies produced by the vaccine as the first defense.  Some virus still gets into cells in the lung, then T-cells attack virus infected lung cells to prevent further spreading of infection to lung cells.   Cancer vaccines do not utilize antibodies.  Cancer is the result of accumulation of mutations of multiple genes, i.e. in average 200 gene mutations in bladder cancers.  As far as I know, there are no drugs (vaccine) to prevent genes from mutating.  Though our body has its own mechanism to repair DNA damage, preventing abnormal cells from replicating, cancers have  evolved to escape from those internal correction mechanisms.  So, at present, cancer vaccines are to kill cancer cells as soon as they arise.

For a cancer vaccine to succeed, identifying which antigens expressed in cancer cells will give the best response from the patient's immune system against the antigens.  I will explain it next.