THE TOP 10 ISSUES THAT CONFRONT THERAPEUTIC CANCER VACCINE DESIGN

Dr. Michael Har-Noy of Hadassah-Hebrew University Medical Center and the founder of Immunovative Therapies, Ltd.  will be a key-note speaker at Immunotherapy World 2016. He has listed his TOP 10 issues that confront design of therapeutic cancer vaccines.  In his address at the conference, Dr. Har-Noy will discuss a “unified field” approach to cancer vaccine design which can address all the listed issues.

 

Cancer vaccine problem #1:  selection of antigen

An antigen is part of a cell’s bar code.  A cell can have innumerable antigens that make up the unique bar code.   Tumors are able to change the antigens over time.  Thus, the more antigens included in the vaccine, the less likely the tumor can hide it’s bar code from immune recognition. Most current cancer vaccines have only one or just a few antigens.

Cancer vaccine problem #2: selection of adjuvant

An immune response against a tumor is elicited by a vaccine containing a source of tumor antigen (bar-code) and an adjuvant (educational and amplification signal).  Two types of immune responses to an antigen are possible: a ‘killer cell response’ or an ‘antibody response’.  A killer cell response is the desired response to eliminate existing cancers. Therefore, adjuvants which direct the immune response toward the killer cell are needed.  It has been difficult to find adjuvants that are capable of directing a killer immune response.  The only FDA approved adjuvant is called “alum”.  Alum is contained in almost all the protective vaccines.  However, alum directs the immune toward an antibody response.  A further complication is that tumors produce proteins, called cytokines, which deviate the immune response to a tumor toward an antibody response. This is a tumor defense mechanism that serves to protect the growing tumor cells from immune destruction.

Cancer problem #3:  mismatched antigen and adjuvant

The killer cell and the antibody work in different ways to recognize and kill tumor cells. The killer cell has a bar code reader called a “T-cell receptor”.   The T-cell receptor can only read antigens that are displayed on the surface of cells in the context of a specialized molecule called “MHC I”.  Whereas, an antibody recognizes antigens expressed on the surface of the cell.  Generally, cell antigens that are displayed in the context of MHC I molecules originate from inside the cell, while antigens recognized by antibodies are on the outer cell membrane. Internally derived antigens presented on MHC I molecules tend to be unique for each cell type, whereas surface antigens can be found on normal tissues as well as cancers.  Most cancer vaccines use antigens that are found on the cell membrane. The antigens selected are usually expressed at a higher density on the tumors cell surface than the same antigens displayed on normal cell surfaces. 

Accordingly, there is often a disconnect between the source of antigen in the vaccine that elicits an immune response and how the resulting immune response will recognize the tumor.  Most vaccines use surface antigens which are good for antibodies, but use adjuvants good for killer cells. The mis-match results in an ineffective vaccine.

For example, if a tumor antigen from the tumor cell surface is isolated and injected with an adjuvant which drives a killer cell response, this could result in large numbers of killer cells programmed to identify the surface antigen to reside in circulation. However, if these killer cells that are programmed to recognize a surface antigen encounter a tumor cell, they will not recognize the tumor because the killer cell can only recognize antigens displayed in the context of MHC I molecules and not surface molecules. If the killer cells do not recognize the tumor cell, they will not kill the tumor cell.

Cancer Vaccine Problem #4:  Imprinting good over bad

Unlike protective vaccine where the immune system has never been exposed to the disease antigens, therapeutic vaccination occurs after the immune system has already encountered the disease. The first time the immune system of a cancer patient encountered the tumor cell, the immune response was not effective in eliminating the disease.  Therefore the existence of cancer is due to a failed immune response.  Accordingly, the re-introduction of the tumor to the immune system through vaccination should not be expected to result in any different response that the original failed response.  Many designers of cancer vaccines assume that cancer is a result of a weak immune response. Therefore, the solution is to ‘boost’ the immune system.  However, immune boosting protocols almost always fail to control tumor growth.  This is likely due to the fact that the resident immune response is a failed immune response.  Boosting the failed immune response only results in a stronger failed response and not in a change in response.  To change the response, a vaccine must not ‘boost’ but rather ‘modulate’.  It is necessary to modulate an immune response from a failed response to an effective response. Once the effective response is created, however, it must be imprinted upon the already failed response. A means to selectively boost only the effective response so it overwhelms the resident ineffective response is required. 

Cancer Vaccine Problem #5: Need Help

Of the two immune system mechanisms for killing cells, the killer cell and the antibody, a killer immune response is the most effective in eliminating tumors.  There are specialized immune cells called “helper cells”, or CD4 cells, which are responsible for directing and orchestrating the type of immune response that will occur upon encounter with an antigen.  There are two types of specialized helper cells, one called a “Th1 cell” ,responsible for directing a killer cell response. The other called a “Th2 cell “, responsible for directing an antibody response. 

Killer cells will not function unless they receive signals from Th1 helper cells.  B-cells producing antibody will not function unless they receive signals from Th2 helper cells. A vaccine that elicits a killer cell response against a tumor, but does not activate Th1 helper cells (or activates Th2 cells instead) will not be effective in causing the killing of tumor cells 

Complicating the situation, most late stage cancer patients have an imbalance in favor of Th2 cells. In fact tumors actively produce substances which deviate an immune response to the tumor away from Th1 and toward Th2.  Accordingly, not only does a therapeutic cancer vaccine need to elicit a killer response with activated Th1 cells, this response must occur in an unfavorable environment dominated by Th2 helper cells and be powerful enough to overcome the Th1/Th2 imbalance.

Cancer Vaccine Problem #6:  Killer Cell Trafficking

Even if a vaccine were able to elicit a killer immune response with activated Th1 cells and the killer cells were able to recognize tumor bar code on MHC I molecules, these cells still would need to move out from the circulation into the tissues where the tumor cells reside in order to kill tumor cells.  Vaccines contain an antigen for target identification and an adjuvant for directing the type of immune response against the target.  However, there usually is not a component that assures that any resulting immune cells traffic to the tumor sites.  Normally, killer immune cells and helper cells circulate in the blood and traffic to the lymph nodes. In order for these cells to leave the circulation and enter tissues (where most metastatic tumors reside), the immune cells need to first mature to be ‘memory cells’ and then the memory cells require activation.  Memory cells can be created by repeated vaccine injections.   The dose of antigen and adjuvant and the frequency of the injections must be optimized in order to create memory cells.  Optimization of these parameters is usually the goal of early vaccine clinical trials. However, while vaccines may be able to be optimized to generate memory cells, usually there is no protocol for activating these cells in order to cause them to traffic to the tumor sites.  Without trafficking to the tumor sites, killer cells can not have a chance to function to kill the tumors. 

Illustrative of this problem, even when large numbers of killer cells are educated and expanded outside the body and then infused back to cancer patients, the overwhelming increase of killer cells in circulation does not usually result in any significant tumor killing effect. 

Cancer Vaccine Problem #7: Tumors cell cloaking

Even if a vaccine were able to educate killer cells to recognize tumor antigens displayed on MHC I molecules and provided activated Th1 cells to provide help to the killer cells, and the killer cells matured to memory cells and the memory killer cells were activated and trafficked to the tumor bed, these cells still would be unable to kill the tumor cells.  This is due to the fact that killer cells recognize tumor antigens in the context of MHC I molecules. However, most human tumor cells internalize their MHC I molecules so they are not displayed for killer cells.  This is a mechanism used by tumor cells to evade immune killer cell attack. Without recognition of tumors antigens via MHC I molecules, the killer cells can not kill the tumor cells.

Cancer Vaccine Problem #8: Tumor cell cloaking II

Even if a vaccine were able to educate killer cells to recognize tumor antigens displayed on MHC I molecules and provided activated Th1 cells to provide help to the killer cells, and the killer cells matured to memory cells and the memory killer cells were activated and trafficked to the tumor bed, and the tumors were made to express MHC I molecules, these cells still would be unable to kill the tumor cells. This is because killer cells require two signals in order to kill.  The first signal is through the T-cell receptor which interacts with the MHC I molecule on the tumor cells.  The second signal is through the interaction of “co-stimulatory” molecules on the killer cells and their counterparts (ligands) on the tumor cells.  The problem is that tumors normally do not display the co-stimulatory molecule ligands.  Without display of these ligands, killer cells can not kill.  Sometimes, however, tumors display co-stimulatory ‘decoy’ ligands.  These are checkpoint molecules. The checkpoint molecules can send a negative signal to the killer cells, so that the killer cell shuts off its killing machinery instead of engaging the machinery and killing the tumor. Checkpoint blockade drugs, such as Yervoy and Opdivo, prevent this negative decoy signal from being sent to killer cells. However, In such case, a positive co-stimulatory signal is still needed in order for killer cells to engage and kill the tumor cell.

Cancer Vaccine Problem #9: Immune Suppression

There are many types of immune cells that function to regulate the immune response.  Immune cells known as T-regulatory (Treg) cells function to suppress killer immune responses. Established tumors promote the maturation and expansion of these Tregs.  Tregs as well as other types of suppressor cells are resident in tumor beds and in the circulation of cancer patients. Accordingly, even if a therapeutic cancer vaccine were able to educate killer cells to recognize tumor antigens displayed on MHC I molecules and provided activated Th1 cells to provide help to the killer cells, and the killer cells matured to memory cells and the memory killer cells were activated and trafficked to the tumor bed, and the tumors were made to express MHC I molecules and co-stimulatory molecules, a method to short circuit the influence of suppressor cells is still needed in order for the killer cells to eliminate tumors.  Suppressor cells are part of the natural immune regulatory system that acts to prevent killer cells from destroying normal tissues (as occurs in autoimmune disease).  Tumors harness these natural suppressor mechanisms in order to evade immune attack. 

Cancer Vaccine Problem #10: “Push-Pull” network

The immune system is analogous to a computer network whereby the computer network consists of many components such as routers, switches, web servers, mail servers, database servers, DNS servers, IDS and firewalls, the immune system consists of many cell types such as helper cells, killer cells, B-cells, monocytes, dendritic cells, NK cells and suppressor cells. A large network like the Internet can have millions of these components. A network like the human immune system can have billions of these components. Computer networks and immune networks are dynamic systems and each time interval their components produce large amounts of event-based data. All these events can, in principle, be collected and analyzed.  A tumor is like a network hacker that seeks to take control of the network and redirect it’s activities.

The numerous cells involved in the cascade of immune events that leads to tumor destruction each express numerous signal proteins and signal receptors on the cell surface.  The interactions of these signal proteins and their receptors send positive and negative signals to the cell nucleus (brain center).  The integration of these signals determines the action of the cells (divide, die, kill, eat debris, process, package, present, etc.). In addition, many of these cells also produce myriads of chemical signals (cytokines, monokines, chemokines) and have receptors for these chemical signals. Chemical signals can condition the systemic and local microenvironments to control and direct the function of immune cell clusters.

Immune networks are dynamic systems that integrate all these positive and negative signals both on an individual cellular level and on a population level within a microenvironments (e.g., in circulation, a lymph node or a tumor bed).  These signals must be received by the various immune cells at a precise moment in time and space (temporal and spatial) in order to complete the immune cascade of events that results in tumor destruction.   Tumors can influence the natural immune cascade by producing or inducing other cells to produce signaling cytokines and chemokines. The tumor cells can also express positive and negative signaling proteins on their cell surface or influence the expression or down regulation of expression of these proteins on other cells in the immune network.  When the immune system receives signals signals intended to disrupt, redirect or stop an immune cascade, the immune network can use its various redundant systems to bypass these attacks and still reach the end goal of tumor killing by various different routes.  However, a tumor has the ability to attack the immune network in a myriad of ways. Eventually the tumor takes control of the immune network at many levels to assure its own survival.  Due to the dynamic structure and function of the immune network, the mechanism that tumors use to successfully survive an immune attack will vary by individual and vary within different tumor beds in the same patient.  When a patient has a tumor, the tumor cells attack the immune network in events that are scattered among the distributed events in the cascade leading to tumor killing. Therefore a critical challenge for vaccine design is to provide a “push” to the immune network in response to a tumor mediated “pull” and a “pull” in response to a tumor mediated “push” that is customized to the individual patient. Due to the complexity of the dynamic immune network that is under active attack by established tumors, it is difficult to conceive of a single therapeutic vaccine injection of an antigen with adjuvant that could so disrupt the negative influence of the tumor to successfully promote a cascade of immune events leading to tumor destruction.

Only the Immunovative strategy of reversing engineering a proven curative immune effect against metastatic cancer (Mirror Effect) which led to the development of an immunomodulatory drug with multiple mechanisms depending on dose, frequency and location of administration (AlloStim) integrated with a protocol and heat shock protein vaccine technology (both in-vivo and in-vitro) can provide the "push-pull" required to create anti-tumor immunity in chemotherapy-refractory patients and overcome systemic and tumor-induced immunosuppression and immunoavoidance mechanisms.

 

 

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Treatment strategy designed to use the power of the human immune system to kill tumors and prevent their recurrence.
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Therapeutic anti-tumor vaccine developed from core break-through technology called the "Mirror Effect™“ which opens a pathway to treating patients with metastatic cancer that have failed all available therapy options.
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