Cancer vaccine
Encyclopedia
The term cancer vaccine refers to a vaccine
that either prevents infections with cancer-causing viruses, treats existing cancer
or prevents the development of cancer in certain high risk individuals. (The ones that treat existing cancer are known as therapeutic cancer vaccines.)
Some types of cancer, such as cervical cancer
and some liver cancers
, are caused by viruses, and traditional vaccines against those viruses, such as HPV vaccine
and Hepatitis B vaccine
, will prevent those cancers. (These anti-viral vaccines are not further discussed in the rest of this article) Other cancers are to some extent caused by bacterial infections (e.g. Stomach cancer and Helicobacter pylori
) and traditional vaccines against cancer causing bacteria are also not currently discussed in this article.
Scientists have also been trying to develop vaccines against existing cancers.
Some researchers believe that cancer cells routinely arise and are destroyed by the healthy immune system; cancer forms when the immune system fails to destroy them.
In a phase III trial of follicular lymphoma
(a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID prolonged remission by 44.2 mo, versus 30.6 mo for the control, at the June 2009 meeting of the American Society of Clinical Oncology.
On April 14, 2009, Dendreon
Corporation announced that their Phase III clinical trial of Provenge, a cancer vaccine designed to treat prostate cancer, had demonstrated an increase in survival. It received U.S. Food and Drug Administration (FDA) approval for use in the treatment of advanced prostate cancer patients on April 29, 2010. The approval of Provenge has stimulated interest in this type of therapy.
Another approach to therapeutic anti-cancer vaccination is to generate the immune response in situ in the patient. This approach has been successful used by BioVex Inc, Woburn, MA with their product OncoVEX GM-CSF. OncoVEX GM-CSF is a version of herpes simplex virus
which has been engineered to replicate selectively in tumor tissue and also to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigen
s released following lytic virus replication providing an in situ, patient specific anti-tumor vaccine as a result. This is currently in Phase 3 trials in melanoma and head and neck cancer following a very high degree of efficacy having been observed in Phase 2 trials. BioVex was purchased by Amgen Inc for $1 billion in January 2011.
On April 8, 2008, New York-based company Antigenics announced that it had received approval for the first therapeutic cancer vaccine in Russia. It is the first approval by a regulatory body of a cancer immunotherapy. The treatment, Oncophage
, increased recurrence-free survival by a little more than a year according to the results of a phase III clinical trial. The approval is for a subset of kidney cancer
patients who are at intermediate risk for disease recurrence. It awaits approval in the US and EU. but will need a new trial for FDA approval.
Most of the cancer vaccines in development are addressing specific cancer types and are therapeutic vaccines. Several cancer vaccines are currently in development by companies such as:
Also ALVAC-CEA vaccine
.
(Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and Favrille Inc (FavId) are examples of cancer vaccine projects that have been terminated due to poor phase III results (despite promising phase II data and strong immune responses).
specific to the tumor and distinct from self-proteins. Selection of the appropriate adjuvant
, molecules that activate antigen-presenting cells to stimulate immune responses, is required. At the present time, only Bacillus Calmette-Guérin
(BCG), aluminum-based salts and a squalene-oil-water emulsion are approved worldwide for clinical use. The effective vaccine also should seek to provide longterm memory to prevent tumor recurrence. Some scientists believe that for total tumor elimination, both the innate and adaptive immune systems should be activated.
s have been divided into two broad categories: shared tumor antigens; and unique tumor antigens. Shared antigens are expressed by many tumors. Unique tumor antigens result from mutations induced through physical or chemical carcinogens; they are therefore expressed only by individual tumors.
In one approach, vaccines contain whole tumor cells, though these vaccines have been less effective in eliciting immune responses in spontaneous cancer models. Defined tumor antigens decrease the risk of autoimmunity but because the immune response is directed to a single epitope
, tumors can evade destruction through antigen loss variance. A process called "epitope spreading" or "provoked immunity" may mitigate this weakness, as sometimes an immune response to a single antigen will lead to development of immunity against other antigens on the same tumor.
s the immune system
can recognize. Furthermore, there are usually only a few viable variants of the virus in question. It is very hard to develop vaccines for viruses that mutate constantly such as influenza
or HIV
.
A tumour can have many different types of cells in it, each with different cell-surface antigens. Furthermore, those cells are derived from the individual with cancer, and therefore display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish the cancer cells from normal cells. Some scientists believe that Renal cancer and melanoma
are the two cancers with most evidence of causing spontaneous and effective immune responses, possibly because they often display antigens that are recognized as foreign. Therefore, many attempts at developing cancer vaccines are directed against these tumors. However, given Dendreon's success in prostate cancer, a disease that never spontaneously regresses, cancers other than melanoma and renal cancer may be equally amenable to immune attack.
However, most clinical trials investigating a cancer vaccine have failed or had very modest responses by standardized oncologic assessment criteria described as the RECIST criteria. The precise reasons are unknown, but possible explanations include:
1) disease stage being treated was too advanced: it is difficult to get the immune system to fight bulky tumor deposits, because tumors actively suppress the immune system using a variety of mechanisms (e.g. secretion of cytokines that inhibit immune activity). The most suitable stage for a cancer vaccine is likely to be early disease, when the tumor volume is low, but the problem there is that clinical trials take upwards of five years and require high numbers of patients to reach measurable end points. The alternative is to target patients with minimal residual disease after de-bulking of the tumor by surgery, radiotherapy or (providing it does not in itself harm the immune system) chemotherapy.
2) escape loss variants (cancer vaccines that target just one tumor antigen
are likely to be less effective. Tumors are highly heterogeneous and antigen expression differs markedly between tumors (even within deposits in the same patient). The most effective cancer vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor being able to mutate and become resistant to the therapy.)
3) prior treatments (numerous clinical trials in the past have treated patients who have received numerous cycles of chemotherapy. Chemotherapy is often myelosuppressive and destroys the immune system. There is little point giving a cancer vaccine to a patient who is immune suppressed).
4) some tumors progress very rapidly and/or unpredictably, and they can literally outpace the immune system. It may take two to three months for an immune response to a vaccine to mature, but some cancers (e.g. advanced pancreatic) can produce marked clinical deterioration, or even death, within this timeframe.
5) many cancer vaccine clinical trials examine immune responses by patients as their primary goal. Correlations are then made, typically showing that the patients who made the strongest immune responses were the ones who lived the longest, and this is taken as evidence that the vaccine is working. The alternative explanation, however, is that the patients who made the best immune responses were the healthier patients with the better prognosis, and they would have survived longest in any event, even without the vaccine. In other words, the immune responses may simply be a simple reflection of a better health status, not an indication that the vaccine had any beneficial effects. As such, these immune 'false friends' may have tempted some to embark on expensive phase III trials without a solid rationale.
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
that either prevents infections with cancer-causing viruses, treats existing cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
or prevents the development of cancer in certain high risk individuals. (The ones that treat existing cancer are known as therapeutic cancer vaccines.)
Some types of cancer, such as cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
and some liver cancers
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
, are caused by viruses, and traditional vaccines against those viruses, such as HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
and Hepatitis B vaccine
Hepatitis B vaccine
Hepatitis B vaccine is a vaccine developed for the prevention of hepatitis B virus infection. The vaccine contains one of the viral envelope proteins, hepatitis B surface antigen . It is produced by yeast cells, into which the genetic code for HBsAg has been inserted...
, will prevent those cancers. (These anti-viral vaccines are not further discussed in the rest of this article) Other cancers are to some extent caused by bacterial infections (e.g. Stomach cancer and Helicobacter pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
) and traditional vaccines against cancer causing bacteria are also not currently discussed in this article.
Scientists have also been trying to develop vaccines against existing cancers.
Some researchers believe that cancer cells routinely arise and are destroyed by the healthy immune system; cancer forms when the immune system fails to destroy them.
Method
One approach to cancer vaccination is to separate proteins from cancer cells and immunize cancer patients against those proteins, in the hope of stimulating an immune reaction that would kill the cancer cells. Therapeutic cancer vaccines are being developed for the treatment of breast, lung, colon, skin, kidney, prostate, and other cancers.In a phase III trial of follicular lymphoma
Follicular lymphoma
Follicular lymphoma is the most common of the indolent non-Hodgkin's lymphomas, and the second most common form of non-Hodgkin's lymphomas overall. It is defined as a lymphoma of follicle center B-cells , which has at least a partially follicular pattern...
(a type of non-Hodgkin's lymphoma), investigators reported that the BiovaxID prolonged remission by 44.2 mo, versus 30.6 mo for the control, at the June 2009 meeting of the American Society of Clinical Oncology.
On April 14, 2009, Dendreon
Dendreon
Dendreon is a Seattle based biotechnology company. Its lead product, Provenge , is an immunotherapy for prostate cancer...
Corporation announced that their Phase III clinical trial of Provenge, a cancer vaccine designed to treat prostate cancer, had demonstrated an increase in survival. It received U.S. Food and Drug Administration (FDA) approval for use in the treatment of advanced prostate cancer patients on April 29, 2010. The approval of Provenge has stimulated interest in this type of therapy.
Another approach to therapeutic anti-cancer vaccination is to generate the immune response in situ in the patient. This approach has been successful used by BioVex Inc, Woburn, MA with their product OncoVEX GM-CSF. OncoVEX GM-CSF is a version of herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
which has been engineered to replicate selectively in tumor tissue and also to express the immune stimulatory protein GM-CSF. This enhances the anti-tumor immune response to tumor antigen
Tumor antigen
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...
s released following lytic virus replication providing an in situ, patient specific anti-tumor vaccine as a result. This is currently in Phase 3 trials in melanoma and head and neck cancer following a very high degree of efficacy having been observed in Phase 2 trials. BioVex was purchased by Amgen Inc for $1 billion in January 2011.
On April 8, 2008, New York-based company Antigenics announced that it had received approval for the first therapeutic cancer vaccine in Russia. It is the first approval by a regulatory body of a cancer immunotherapy. The treatment, Oncophage
Oncophage
Oncophage is a personalized cancer vaccine by the American company Antigenics Inc. that is currently evaluated in multiple clinical trials. It has been granted fast track and orphan drug designations from the US Food and Drug Administration for kidney cancer, metastatic melanoma, and...
, increased recurrence-free survival by a little more than a year according to the results of a phase III clinical trial. The approval is for a subset of kidney cancer
Kidney cancer
Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...
patients who are at intermediate risk for disease recurrence. It awaits approval in the US and EU. but will need a new trial for FDA approval.
Most of the cancer vaccines in development are addressing specific cancer types and are therapeutic vaccines. Several cancer vaccines are currently in development by companies such as:
- Panacela Labs, Inc. a Cleveland Biolabs (CBLI) Subsidiary: MOBILAN Adenovirus-based treatment inducing immune response. Ready for final stage of preclinical development.
- DendreonDendreonDendreon is a Seattle based biotechnology company. Its lead product, Provenge , is an immunotherapy for prostate cancer...
Corp (DNDN) (NeuvengeNeuvengeNeuvenge, Lapuleucel-T , is a therapeutic cancer vaccine in development by Dendreon . It uses the "immunotherapy platform approach" first successfully demonstrated on the U.S. Food and Drug Administration -approved TCV Provenge...
, for HER2/neuHER2/neuHER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
expressing cancers such as BreastBreastThe breast is the upper ventral region of the torso of a primate, in left and right sides, which in a female contains the mammary gland that secretes milk used to feed infants.Both men and women develop breasts from the same embryological tissues...
, BladderBladderBladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...
, colonColon (anatomy)The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, Ovarian), - Celldex Therapeutics (CDX110, CDX1307 and CDX1401),
- Heat Biologics ImPACT Therapy against NSCLC and other cancers
- Geron Corporation (GRNVAC1),
- BN ImmunoTherapeutics (PROSTVAC),
- GlobeImmune (Tarmogens, GI-4000),
- AdvaxisAdvaxisAdvaxis is a clinical-stage biotechnology company developing the next generation of immunotherapies for cancer and infectious diseases. Their novel platform technology generates a comprehensive immune response by serving as its own adjuvant, directing antigen presentation, increasing tumor...
(ADXS11-001Lovaxin CLovaxin C is a live attenuated Listeria cancer vaccine that is under investigation and has entered clinical trials. It is under development at Advaxis. Note: Lovaxin C has been renamed ADXS11-001-Background:...
, ADXS31-001, ADXS31-164), - Accentia Biopharmaceuticals majority owned subsidiary BiovestBiovestBiovest International, Inc is a Tampa based biotechnology company that is majority-owned subsidiary of Accentia Biopharmaceuticals. Their main product candidate, BiovaxID, is a cancer vaccine that treats Follicular lymphoma.-BiovaxID:...
International (BiovaxID in phase III), - Apthera, Inc. (NeuVax),
- Avax TechnologiesAvax TechnologiesAvax Technologies, Inc is a Philadelphia based biotechnology company whose most advanced product candidate is MVax for melanoma. MVax is a cancer vaccine that received a Special Protocol Assessment agreement with the FDA in October 2006, and subsequently began a Phase III registration clinical...
[AC Vaccine], - Generex Biotechnology through its wholly owned immunotherapeutic subsidiary Antigen Express (Ae-37).
- Immatics biotechnologies (e.g. IMA901 for renal cancer)
- Scancell Holdings, (SCIB1SCIB1SCIB1 is a genetically-engineered cancer vaccine being developed by Scancell Holdings Plc as a treatment for melanoma.-External links:*...
) - Merck, in 2009, is starting phase III trials of StimuvaxStimuvaxStimuvax is an investigational therapeutic cancer vaccine designed to induce an immune response to cancer cells that express MUC1, a glycoprotein antigen widely expressed on common cancers. MUC1 is over-expressed on many cancers such as lung cancer, breast cancer, prostate cancer and colorectal...
for breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. It had promising results from a phase IIB trial for inoperable lung cancerLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
. - Oncotherapy Science (The first world peptide vaccines are produced. Some of vaccines are now in phase 2&3)
Also ALVAC-CEA vaccine
ALVAC-CEA vaccine
ALVAC-CEA vaccine is a cancer vaccine containing a canary pox virus combined with the carcinoembryonic antigen human gene.A phase I trial in 118 patients showed safety in humans.- External links :...
.
Approved Therapeutic Vaccines
- Antigenics Inc. (OncophageOncophageOncophage is a personalized cancer vaccine by the American company Antigenics Inc. that is currently evaluated in multiple clinical trials. It has been granted fast track and orphan drug designations from the US Food and Drug Administration for kidney cancer, metastatic melanoma, and...
, approved in Russia in 2008 for kidney cancerKidney cancerKidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...
), - DendreonDendreonDendreon is a Seattle based biotechnology company. Its lead product, Provenge , is an immunotherapy for prostate cancer...
Corp (Sipuleucel-T, Provenge, FDA approved April 2010 for metastatic hormone-refractory prostate cancer).
Abandoned
Cell Genesys (GVAX), CancerVaxCancerVax
CancerVax was an American pharmaceutical company founded in 1998 by Donald Morton. The company sought to develop a vaccine for cancer, and had candidates for melanoma reach phase III clinical trials. When those trials proved unsuccessful in 2005, the company soon underwent a reverse takeover with...
(Canvaxin), Genitope Corp (MyVax personalized immunotherapy), and Favrille Inc (FavId) are examples of cancer vaccine projects that have been terminated due to poor phase III results (despite promising phase II data and strong immune responses).
Desired characteristics
Effective cancer vaccines must resolve several challenges. Cancer vaccines seek to target an antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
specific to the tumor and distinct from self-proteins. Selection of the appropriate adjuvant
Immunologic adjuvant
In immunology, an adjuvant is an agent that may stimulate the immune system and increase the response to a vaccine, without having any specific antigenic effect in itself. The word “adjuvant” comes from the Latin word adiuvare, meaning to help or aid...
, molecules that activate antigen-presenting cells to stimulate immune responses, is required. At the present time, only Bacillus Calmette-Guérin
Bacillus Calmette-Guérin
Bacillus Calmette-Guérin is a vaccine against tuberculosis that is prepared from a strain of the attenuated live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured in an artificial medium for 13 years, and also prepared from...
(BCG), aluminum-based salts and a squalene-oil-water emulsion are approved worldwide for clinical use. The effective vaccine also should seek to provide longterm memory to prevent tumor recurrence. Some scientists believe that for total tumor elimination, both the innate and adaptive immune systems should be activated.
Antigen candidates
Tumor antigenTumor antigen
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...
s have been divided into two broad categories: shared tumor antigens; and unique tumor antigens. Shared antigens are expressed by many tumors. Unique tumor antigens result from mutations induced through physical or chemical carcinogens; they are therefore expressed only by individual tumors.
In one approach, vaccines contain whole tumor cells, though these vaccines have been less effective in eliciting immune responses in spontaneous cancer models. Defined tumor antigens decrease the risk of autoimmunity but because the immune response is directed to a single epitope
Epitope
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 recognizes the epitope is called a paratope...
, tumors can evade destruction through antigen loss variance. A process called "epitope spreading" or "provoked immunity" may mitigate this weakness, as sometimes an immune response to a single antigen will lead to development of immunity against other antigens on the same tumor.
Hypothesized Problems
A vaccine against a particular virus is relatively easy to create. The virus is foreign to the body, and therefore will express antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
can recognize. Furthermore, there are usually only a few viable variants of the virus in question. It is very hard to develop vaccines for viruses that mutate constantly such as influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
or HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
.
A tumour can have many different types of cells in it, each with different cell-surface antigens. Furthermore, those cells are derived from the individual with cancer, and therefore display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish the cancer cells from normal cells. Some scientists believe that Renal cancer and melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
are the two cancers with most evidence of causing spontaneous and effective immune responses, possibly because they often display antigens that are recognized as foreign. Therefore, many attempts at developing cancer vaccines are directed against these tumors. However, given Dendreon's success in prostate cancer, a disease that never spontaneously regresses, cancers other than melanoma and renal cancer may be equally amenable to immune attack.
However, most clinical trials investigating a cancer vaccine have failed or had very modest responses by standardized oncologic assessment criteria described as the RECIST criteria. The precise reasons are unknown, but possible explanations include:
1) disease stage being treated was too advanced: it is difficult to get the immune system to fight bulky tumor deposits, because tumors actively suppress the immune system using a variety of mechanisms (e.g. secretion of cytokines that inhibit immune activity). The most suitable stage for a cancer vaccine is likely to be early disease, when the tumor volume is low, but the problem there is that clinical trials take upwards of five years and require high numbers of patients to reach measurable end points. The alternative is to target patients with minimal residual disease after de-bulking of the tumor by surgery, radiotherapy or (providing it does not in itself harm the immune system) chemotherapy.
2) escape loss variants (cancer vaccines that target just one tumor antigen
Tumor antigen
Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful in identifying tumor cells and are potential candidates for use in cancer therapy.- Mechanism of tumor antigenesis:...
are likely to be less effective. Tumors are highly heterogeneous and antigen expression differs markedly between tumors (even within deposits in the same patient). The most effective cancer vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor being able to mutate and become resistant to the therapy.)
3) prior treatments (numerous clinical trials in the past have treated patients who have received numerous cycles of chemotherapy. Chemotherapy is often myelosuppressive and destroys the immune system. There is little point giving a cancer vaccine to a patient who is immune suppressed).
4) some tumors progress very rapidly and/or unpredictably, and they can literally outpace the immune system. It may take two to three months for an immune response to a vaccine to mature, but some cancers (e.g. advanced pancreatic) can produce marked clinical deterioration, or even death, within this timeframe.
5) many cancer vaccine clinical trials examine immune responses by patients as their primary goal. Correlations are then made, typically showing that the patients who made the strongest immune responses were the ones who lived the longest, and this is taken as evidence that the vaccine is working. The alternative explanation, however, is that the patients who made the best immune responses were the healthier patients with the better prognosis, and they would have survived longest in any event, even without the vaccine. In other words, the immune responses may simply be a simple reflection of a better health status, not an indication that the vaccine had any beneficial effects. As such, these immune 'false friends' may have tempted some to embark on expensive phase III trials without a solid rationale.
Recommendations for success
In January 2009, a review article was published in Expert Reviews in Anticancer Therapy (Vol 9, #1, pages 67–74) which highlighted past program failures and made recommendations for success as follows:- 1. Target settings with a low or very low burden of disease; it is clear that vaccines will not work in patients with advanced metastatic disease.
- 2. Conduct randomized Phase II trials so that the Phase III program is sufficiently powered – resist the temptation to leap into Phase III prematurely.
- 3. Do not randomize antigen plus adjuvant versus adjuvant alone. The goal is to establish clinical benefit of the immunotherapy (i.e.,adjuvanted vaccine) over the standard of care, not over standard of care plus adjuvant. The adjuvant may have a low-level clinical effect that would skew the statistical powering of the trial, increasing the chances of a false negative.
- 4. Base development decisions on clinical data, not just immune responses. Time-to-event end points are more valuable and clinically relevant. To date, immune responses have not been predictive of clinical benefit. It is possible that the ability to mount an immune response is merely a prognostic factor that identifies patients with pretreatment characteristics that favor longer survival.
- 5. Regulatory compliance needs to be designed into the program from inception; invest in the manufacturing process and product assays early. It is much more difficult to retrofit.
External links
- Cancer Immunotherapy Consortium (has newsletter with good summary of CV news e.g. clinical trials)
- Cancer Vaccine Collaborative (coordinated early-phase clinical trials of therapeutic cancer vaccines)
- International Society for Biological Therapy of Cancer
- Association for the Immunotherapy of Cancer
- BioBusiness.TV Cancer Immunotherapy Series - Scientific, Clinical, Industrial, and Financial Perspectives