Immunotherapies

Introduction

Advances in cancer research have provided a deeper understanding of the complex interactions that occur between the immune system and tumor cells as well as the many tumor evasion strategies. Cancer cells continue to evolve and find new ways to evade and outsmart the immune system, resulting in the continuous need for the development of novel therapeutic options focused on enhancing the functionality of the immune system and anti-tumor immunity. The greatest weapon cancer cells now use to avoid detection and thrive is the ability to alter the function and regulation of the immune system. Some cancer cells suppress factors involved in the promotion of the immune response and enhance other factors known to inhibit the immune response.

While a variety of treatment modalities are currently used to fight cancer, the aim of immunotherapy is to enhance the ability of a patient’s immune system to fight back and target the tumor cells. Immunotherapy provides an option for complex and late stage cancer patients, where other traditional therapies have demonstrated only modest at best improvements. These therapies can be classified as active — directing the patient’s immune system to interact directly with tumor cells — or passive, enhancing the anti-cancer response. Immunotherapy is not a quick fix; in some instances, these treatment options can take even longer than traditional therapies to see a response, time that that may not be an option for late stage cancer patients.

Despite the potential for prolonged time until response, immunotherapy has been shown to be an effective treatment for certain cancers where previous chemotherapy and radiation have shown little to no effect. Additionally, there is the potential that boosting a patient’s own immune system will allow it to recognize recurrent cancer cells and enhance the efficiency of the immune system to fight back against these types of cancers.

The potential exists that the opposite effect can also hold true, where cancer cells develop a resistance to the effects of immunotherapy and/or over stimulation of the immune system during prior immunotherapy results in an ineffective immune response when the tumor returns. The variation in response rates to immunotherapy can be attributed to several factors including the specificity needed to elicit the desired immune response, overcoming the evasion tactics the cancer cells are using and ensuring the activated immune cells are able to find the malignant tissues.

With the advances in immunotherapy, more and more therapies are being tested in clinical trials and approved by the FDA to treat a variety of cancers. However, the success of immunotherapies is highly dependent on the type and grade of cancer and expression of critical immunological and molecular biomarkers. While the development of new immunotherapy agents is rapidly growing, this module will provide an overview of the main categories and current status of immunotherapies.

Non-targeted (Non-specific) Immunotherapies

While it can be given as monotherapy, it is more often used concurrently or just after other traditional cancer treatments including radiation and/or chemotherapy.

Cytokine Therapy

This mode of therapy involves systemically infusing specific cytokines, interferons and interleukins, to boost the immune response. Currently, the two main cytokines used during cancer treatment are Interferon alpha (IFN-alpha), which slows cancer cell growth, and interleukin-2 (IL-2), which signals the immune system to produce additional cells to fight against cancer. IL-2 is currently used in the treatment of melanomas and kidney cancers that have metastasized to other regions of the body. IFN-alpha is also used in the treatment of melanoma and kidney cancer, in addition to certain leukemias and lymphomas. Often cytokine therapy is used in combination with other immunotherapies to enhance their effectiveness.

Example of FDA Approved Therapy

Aldesleukin (Proleukin; Boehringer Ingelheim, Prometheus Laboratories) is a recombinant form of IL-2 with similar immune activity to the natural IL-2 produced by the immune system. Currently, the FDA has approved Proleukin for the treatment of advanced and metastatic melanoma as well as metastatic renal cell carcinoma (RCC). IL-2 therapy enhances the immune response against tumor cells by blocking reproduction of cancer cells, increasing production of white blood cells that attack tumors, and stimulating the release of chemicals from cancer cells to attract additional immune cells to attack the cancer.

The exact mechanism by which aldesleukin induces an anti-tumor response is not fully understood but has demonstrated an overall response rate of 16% in metastatic melanoma and 15% metastatic RCC. Aldesleukin is associated with a number of toxicities, and as such may not be appropriate for all patients.

Targeted Immunotherapies: Monoclonal Antibodies, Checkpoint Inhibitors, Therapeutic Vaccines

This class of immunotherapies work by targeting the differences within cancer cells compared to normal, healthy cells. As these types of therapies do not normally affect healthy cells, the side effects are often quite different from that of non-targeted and chemotherapy treatments. These therapies work by triggering the immune system to specifically focus in on cancer cells or from inside the cell to result in cell death.

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Monoclonal Antibodies

One of the body’s own defense strategies is the production of antibodies, proteins that bind to specific antigens on the surface of the cancer cells, thereby marking them for destruction by immune cells. Researchers are designing antibodies that target specific antigens on cancers cells to boost the immune response, called monoclonal antibodies.

Monoclonal antibodies are an example of active immunity and are being used to treat cancer (breast, lymphoma, and colorectal) in addition to a variety of other diseases. Monoclonal antibodies can be used to block the production of abnormal proteins found in cancer cells, attach to proteins on the surface of cancer cells and flag the cells for destruction, or by inhibiting or slowing down the pathways that cancer cells use for growth.

They can also be conjugated to therapeutic drugs that have cytotoxic effects on cancer cells. However, one caveat that must be considered is for monoclonal antibodies to be effective, researchers must identify the exact antigen for specific cancer cells present in patient’s body. This means this treatment option is only effective in certain cancer types.

Example of FDA Approved Therapy

Nivolumab (Opdivo, Bristol-Myers Squibb) is a human monoclonal antibody against programmed death-1 (PD-1) inhibitory receptor expressed on a variety of immune cells. Binding of PD-1 to one of its two ligands, PD-L1 or PD-L2, results in suppression of the immune response. Nivolumab has a high specificity and affinity for the PD-1 receptor and its blockage of the PD-1/PD-L1 or PD-L2 inhibitory pathway, which leads to increased immune system regulation.

Nivolumab is approved both as a monotherapy and in use with other therapeutic agents in a variety of cancer types; however, the use of PD-L1 as a biomarker is still heavily debated.

Checkpoint Inhibitors - Pathway Specific

As discussed in module 3, the different pathways elicited by the immune system are regulated by various checkpoint proteins and/or factors that can stimulate or inhibit the immune response to stimuli. Targeted immunotherapies primarily focus on checkpoint inhibitors as a way of passive immunity and are a variant of monoclonal antibodies discussed above.

Immune checkpoint inhibitors, as you may recall, work by slowing down or stopping an overly active immune response with the potential to damage healthy cells in addition to the cancer cells that initiated the response. These inhibitors work by preventing T cells from interacting and thereby mounting an immune response against other cells.

Tumor cells exploit this mechanism and deactivate tumor-infiltrating lymphocytes (TILs) thus preventing them from targeting tumor cells. One of the most well-known pathways exploited by tumor cells is PD-1/PD-L1. PD-1 receptor is expressed on the surface of activated T cells upon binding with PD-L1 on the surface of healthy cells, a signal is sent to prevent T cells from attacking normal cells. Some tumor cells overexpress PD-L1 to bind to activated T cells and render them inactive and ineffective. Therapies that target immune checkpoint inhibitors are not interacting directly with tumor cells, they are targeting either PD-1 or PD-L1 to inhibit the binding, thereby enhancing the immune response against cancer cells.

Example of FDA Approved Therapy

Pembrolizumab (Keytruda, Merck) operates in a similar manner to nivolumab; it is a highly selective human monoclonal antibody that targets the PD-1 receptor on the cell surface. Pembrolizumab enhances the activation of T-cell mediated immune response against cancer cells by inhibiting the binding of PD-1 produced by the tumor cell from binding to its receptor. Pembrolizumab has been used across a variety of cancer types both as a monotherapy and in combination with other anti-cancer pharmacotherapy as well as in all lines of therapy.

Therapeutic Vaccines

Therapeutic vaccines contain whole or fragments of cancer cells or antigens associated with a specific type of cancer. They are designed to expose the immune system to a specific antigen to stimulate an immune response to recognize and destroy cancer cells containing that antigen. A patient’s immune cells can be removed and used to create the vaccine that will then be injected back into the body to enhance the immune response to inhibit cancer growth, shrink tumor, prevent recurrence, and potentially eliminate cancer cells all together. These vaccines can often be combined with other therapeutic agents to aid in boosting the immune system.

Some cancers are also caused by viruses, for instance human papillomavirus (HPV) strains have been linked to cervical, anal, throat, vaginal, vulvar and penile cancers. Thus, vaccinating patient populations at high risk for developing certain cancers helps protect against infection and the potential development of the associated cancers. Vaccines for HPV have been shown to significantly reduce the likelihood of developing cervical cancer. These types of preventive vaccines do not target cancer cells directly as they have not formed yet. While immunotherapeutic vaccines work by signaling the immune system to mount a direct attack on specific cancer cells currently in the body.

Example of FDA Approved Therapy

Sipuleucel-T (Provenge, Dendreon Pharmaceuticals LLC) is FDA approved for the treatment of advanced prostate cancer. Provenge is made by harvesting antigen presenting cells and dendritic cells from a patient and then modifying them in the laboratory to immune vaccine to be re-introduced in the patient. The vaccine then stimulates the T-cell immune response in the body to target the prostatic acid phosphatase antigen highly expressed on most prostate cells.

Targeted Immunotherapies: Adoptive Cell Therapies, Oncolytic Virus Therapy

Adoptive Cell Therapies

These therapies use patients’ own immune cells to mount a stronger attack on tumors by increasing the number and effectiveness of the body’s own immune cells thus resulting in a more powerful immune response against cancer.

Main types of adoptive cellular therapy:

Chimeric antigen receptor (CAR) T-cell Therapy

T cells removed from patient’s blood are altered in the laboratory to add specific man-made receptors (CAR) to aid the T cells in identifying specific cancer cells. These altered T cells are then grown in the laboratory to increase in number and then returned to the patient’s body where they seek out and destroy the specific cancer. Prior to the modified T cells being returned to the patient, they must undergo chemotherapy or radiation to deplete the patient’s unaltered immune cells, as they might impede the modified T cells from effectively fight cancer cells.

This type of therapy has been shown to be successful in cancer cells where chemotherapy had failed in the past for some types of lymphomas (acute lymphoblastic leukemia and B- Cell lymphoma) and relapsed or hard to treat leukemia.

Example of FDA Approved Therapy:

Tisagenlecleucel (Kymriah, Novartis) is a CAR T-cell Therapy approved for certain types of lymphomas in children and adults. T cells that are taken from a patient are turned into Kymriah CAR T-cells that when returned to the patient are able to recognize antigens on B-cells and destroy them, including those containing cancer. Two severe side effects that are seen with CAR Ttherapy are cytokine release syndrome (CRS), an acute systemic inflammatory reaction characterized by fever and multiple organ dysfunction, and neurological toxicities.

CAR natural killer (NK) cell Therapy

Tumor cells are known to have adapted mechanisms to avoid detection and inhibit the effectiveness of NK cells to identify and kill abnormal cells thereby impeding the immune response. Similar to CAR T therapy, NK cells are removed and engineered in the lab to better identify and kill specific cancer cells. However, the CAR-NK the cells are not required to be matched to a specific patient. While CAR T-cell therapies have already been approved by FDA, CAR NK-cell therapy is still novel immunotherapy only available through clinical trials.

Tumor-infiltrating lymphocyte (TIL) Therapy

TILs are white blood cells that play an important role in anti-tumor immunity that express a variety of different antigens to regulate the immune response and suppress tumor growth. Research has shown that an increase in the expression of immune cells correlates with more favorable clinical outcomes in malignant cancers including colorectal, lung and breast cancer. Expression of TILs serve as prognostic biomarker in various cancers and thus provide a new avenue for targeted immunotherapy. Similar to CAR T-cell therapy, TIL therapy uses T cells isolated from a patient’s surgically removed tumor and expanded in the lab, significantly increasing the number of TILs, which are normally very low, prior to reintroducing them in the patient to enhance their function against the tumor.

Endogenous T-cell (ETC) Therapy

Naturally expressed tumor reactive T cells are collected from a patient’s blood, filtered to select and enhance only those T cells that are able to recognize cancer cells and expanded in the lab prior to reintroducing them in the patient. While this was originally a very labor-intensive process, research has made significant head way in isolating and enhancing the expression of these T cells. Small initial clinical trials have shown complete and durable response in metastatic patients who have failed traditional chemotherapies and even immune checkpoint immunotherapies.

Oncolytic Virus Therapy

This type of therapy uses a non-pathogenic, genetically modified virus that aids the immune system in destroying cancer cells without harming healthy cells. The virus is directly injected into the tumor where it is able to enter the cancer cells and replicate uncontrollably until the cancer cell bursts and dies. Cancer cells release antigens upon apoptosis that trigger the immune system to mount a targeted response against all cancer cells with the same antigens.

Example of FDA Approved Therapy

Talimogene laherparepvec (T-VEC), an oncologic vaccine therapy approved to treat advanced melanoma skin cancer. It is derived from a genetically modified herpes virus and is injected directly into the melanoma cells where it continuously replicates causing the tumor cells to rupture and die. The exact mechanism in the immune system has not been fully elucidated, however it is believed that in addition to its local effects on the tumor cells it causes an immune response in the body against melanoma. This is thought to work by two different mechanisms.

When T-Vec is administered, it releases new viral particles that can trigger increased activity in the immune system in the location of the tumor, and lead to tumor cell death. These dying tumor cells release antigens which prime the immune system to fight these tumor cells at distant sites or during reoccurrence.

Single vs. Combination Immunotherapies

While immunotherapies have made great strides in the fight against cancer, it is not a one-size-fits-all situation. Different types of immunotherapy have distinct side effects, and some are more effective for certain cancers than others. In addition, a patient’s overall health, strength of their immune system, and the type of cancer all play a role in which immunotherapy is available and will have the greatest chance of being effective.

After considering all relevant factors, including potential autoimmune toxicity, it may be determined a single or combination therapy regimen, including all standard and novel cancer therapies (chemotherapy, radiation, molecularly targeted therapies), is warranted to improve the likelihood of successful treatment. The potential synergy provided by combination therapies could make the tumor more immunogenic, thus enhancing the effectiveness of immunotherapy.

Radiation therapy has been shown to stimulate immune mediators thereby enhancing anti-tumor immune response. Combining radiation with immunotherapy could enhance the efficacy seen with single agent immunotherapy treatments. Combination therapies may allow for more personalized cancer treatment in order to provide the maximum potential benefits of each therapeutic agent.

Advances in immunotherapy treatments are aimed at the potential for initiating a self-sustaining immune response against cancer cells resulting in long-term clinical benefits and reduced incidence of recurrence. While single immunotherapy treatment regimens have shown increasing response rates and durability across all cancer types, a high percentage of patients still fail to respond and the potential for tumors to become resistant over time to these agents still exists.

Therefore, research has turned its focus to the potential of combining immunotherapies with current clinical therapies in addition to other immunotherapy agents in hopes of improving response rate and long-term outcomes for patients. However, combination therapies have their own clinical and economic considerations that must not be overlooked.

Enhancing the immune response has the potential to send the immune system into overdrive thus resulting in serious and sometimes critical autoimmune reactions that can be further exacerbated by the combination with another therapy with similar effects on the immune response. Additionally, single agent immunotherapy alone is expensive, thus using another therapeutic agent increases this already elevated cost.

Future studies need to consider these challenges and potential alterations in the dose of therapies when combined with other therapeutic agents, sequence of therapies, selection of a meaningful endpoints, and selection of appropriate patient populations.

While immune checkpoints are used to prevent T cells from turning against normal cells, tumors have found ways to exploit these pathways complicating the potential therapeutic mechanisms. Nonetheless, currently, combination immunotherapy regimens are often targeted at immune checkpoint inhibitors, PD1/PD-L1 axis and cytotoxic T-lymphocyte antigen 4 (CTLA-4). The combination of PD-1 and CTLA-4 inhibitors are currently being assessed in clinical trials for multiple malignancies, including stomach, breast, bladder, pancreatic, renal, lung and ovarian cancers. In addition, phase 1 and 2 studies are underway combining PD-1 with radiation therapy with promising preliminary results.

Example of FDA Approved Therapy

Pembrolizumab is often used in combination therapy regimes. There are over 1,700 clinical trials investigating pembrolizumab in combination with other cancer therapies. Currently, pembrolizumab is approved in combination with chemotherapy, carboplatin and paclitaxel, as a first line treatment of patients with metastatic squamous non-small cell lung cancer and has shown longer overall and progression free survival in patients then chemotherapy alone.