The difference between passive and active immunotherapy and their impact on cancer treatment.

The focal point for cancer treatment is using a combination of conventional therapies: chemotherapy, radiotherapy and surgery. In most cases, they are effective in treating primary tumours; however, they inefficiently prevent metastasis through disseminated tumour cells. This initiated a promising approach towards immunotherapy as the knowledge and understanding of the immune system increased especially how it can be harnessed to defeat many cancers. According to the National Cancer Institute, immunotherapy is defined as a form of biological therapy that utilizes substances to either activate or inhibit the immune system to aid the body to eradicate cancer and other diseases. There are two types of immunotherapies: active and passive where both approaches can either be non-specific or specific. Non-specific immunotherapies induce a general immune response whereas specific immunotherapies induce a particular immune response to a specific antigen.

The differences between active and passive immunotherapy is summarised in Table 1. Active immunotherapy activates the host’s immune system to induce its own response. In the laboratory, tumour cells are examined and antigens are recognised. This is followed by creating a treatment that would generate a tumour-specific immune response using a combination of cytotoxic T-cell and humoral effector processes. Alternatively, in non-specific active immunotherapy, agents are utilized to co-ordinate a general immune response. Examples of agents include: interleukin-2, interferon-12 and Bacillus Calmette-Guerin (BCG).  Interleukin-2 and interferon-12 are cytokines whereas BCG is a bacterium responsible for tuberculosis. Additionally, active immunotherapy has an immunological memory.

In contrast, passive immunotherapy does not have an immunological memory. There is a temporary anti-tumour effect and chronic administration may be needed. The host immune’s response is initiated by external antibodies or other immune components such as checkpoint inhibitors and cytokines that are generated in a laboratory. This consequently enhances the pre-existing immune response in combating infection and delivers immunity against a disease.

Table 1: A comparison of active and passive immunotherapy. There are differences between both types of therapy. Amongst them are protection, memory and method of administration.

 

Factor Active Immunotherapy Passive Immunotherapy
Protection Not all individuals who receive the recommended vaccine dose have a protect immune response. There is immediate protection.The timing of when injection takes place is vital and is dependent on the form of infection.
Immunological memory Induces immunological memory. Does not induce immunological memory due to passive injection of immune sera/antibodies.
Immunosuppressed individuls It is a disadvantage for those whom are immunosuppressed. It can be an advantage for individuals with low immunity. However, it depends on the function of natural killer cell, macrophage and neutrophil.
Duration of protection The immune cells are long-lasting for instance plasma cells. This results in constant protection.Durable effect after treatment is stopped. Generally only offers short-term protection. Short-lived anti-tumour effect; chronic administration may be needed.
Administration Different routes Needs to be administered systemically
Immune response Stimulates host immune system Enhances pre-existing immune response
Examples Cancer vaccines, Cellular immunotherapy Checkpoint inhibitors. Monoclonal antibodies, Cytokines

 

One of the technologies that are being developed to augment the immune response in passive immunotherapy is adoptive transfer. It refers to therapies that entail transfer of immune components that can induce a specific immune response which directly goes into effector phase.  For example, monoclonal antibodies (MAbs) identifies and associates to particular proteins on cell surface. They have different anti-tumour activities as illustrated in Figure 1. Many MAbs are licensed due to its effectiveness and are summarised in Table 2. Some MAbs augment immune response by binding to cancer cells aiding immune cells to recognise them. For instance Rituximab licensed for non-Hodgkin lymphoma. Another method is by blocking signals from growth factor receptors who normally direct tumour cells to survive and proliferate. For instance, Herceptin antibody targets human epidermal growth factor receptor 2 (HER-2) proteins in breast and stomach cancer. Additionally, some MAbs are conjugated to radiation or drugs where they can transmit these to cancer cells such as Ibritumomab utilized in non-Hodgkin lymphoma. Moreover, some MAbs are still in clinical trials, for instance Nexavar; a multi-kinase inhibitor is in randomised trials and has shown enhancement in time to progression from 12-24 weeks for patients with advanced hepatocellular carcinoma.

Table 2 Monoclonal antibodies licensed for use. Unconjugated antibodies are shaded yellow whereas conjugated antibodies are shaded blue.

Generic Name Trade name Species of Origin Isotype Toxic Payload Target Indication
Bevacizumab Avastin Murine-human Chimeric IgG1 N/A Vascular Endothelial Growth Factor Lung, Breast. Colorectal Cancers
Ibritumomab tiuxetan Zevalin Murine IgG1 Yittrium CD20 Lymphoma
Trastuzumab Herceptin Humanized IgG1  N/A HER2 Breast cancer
Rituximab   Human IgG1      
Cetuximab Erbitux Murine-human Chimeric IgG1 N/A EGF Receptor Colorectal Cancer
Alemtuzumab Campath-1H Humanized IgG1 N/A CD52 Chronic
Rituximab Rituxan Murine-human Chimeric IgG1 N/A CD20 LymphomaSeveral type sof leukaemia
Tositumomab Bexxar Murine IgG2a Iodine CD20 Lymphoma
Gemtuzumab Myelotarg Human IgG4 Calicheamicin CD33 Acute myeloid leukaemia

 

Furthermore, how monoclonal antibodies augments immune response can be seen via chimeric antigen receptors (CARs) technology. CARs illustrated in Figure 2 are recombinant receptors whose structure consists of three generations and there is likely to be an armoured fourth generation. They bind to antigens and activate T-cells. They may associate with cytokines, co-stimulatory receptors or ligands to increase T-cell potency, safety and specificity. Chronic lymphoid leukaemia (CLL), a cancer of the lymphocytes, is an example of where CAR technology has been used. Formerly, there have been attempts to utilize genetically-modified T-cells to suppress tumour progression but had failed. However, when lymphocytes beared a CAR; it bypassed limitations faced due to CAR’s co-stimulatory domain where engineered lymphocytes enhanced tumour rejection activity in a CLL patient. Major expansion and long-term survival post in vivo also occured.

Additionally, CARs have been generated against PSMA antigen; a type II membrane protein that is over-expressed in prostate carcinoma. They utilize single-chain fragment variable (scFv) obtained from the anti-PSMA antibody; J591. scFv is a non-covalent heterodimer that entails heavy and light chain variable domains used to generate recombinant scFv antibodies. scFv was associated to the following intracellular-signalling domains: Z, 28Z, BBZ and 28BBZ. Findings indicated that T-cells who harbour P28BBZ CAR in vitro can specifically eradicate PSMA-positive endothelial cells; impairing tumour growth.

Despite in its infancy, advancement in techniques such as cell-processing, cellular immunology and synthetic biology fields provided a route for CARs’ clinical applications.  Researchers designed a novel functional CAR, TanCAR, that mediated T-cell reactivity, increased effector function and kept T-cell’s cytolytic role after losing a target molecule. This could be utilized in targeting tumour microenvironment, reduce antigen escape and enhance effector cells’ specificity for malignant versus normal target cells.

However, MAbs has not been successful as presumed. The purpose of MAbs and other targeted immunotherapies was to identify a ‘magic bullet’ that would eliminate tumour cells. To this day, it has not been found. Nevertheless taking in consideration the complexity of cancer, it is not surprising. Products were not usually specific as theoretically believed and cytoxicity levels increased when administrating with high doses. CARs can cause cytokine-release syndrome where injected T-cells undergo a mass cytokine release into the blood which can cause fevers and hypotension. This implies the downside of MAb application.

Another technology utilized to augment immune response is adoptive cell transfer (ACT). It consists of causing the patient’s own immune cells (e.g. tumour-specific T-cells) to identify and destroy the tumour whilst keeping normal cells healthy. Although it is currently in clinical trials, treatments based upon these cells had a positive outcome in patients with advanced cancer especially those undergoing bone marrow transplantations whereby the tumour remission level was higher in allogeneic transplantations than autologous transplantations. This is partially due to transfer of T-cells that stimulate tumour regression efficiently.

Metastatic melanoma (MM) is an example of a cancer where ACT has been used. It is where melanoma cells (ocular, cutaneous, mucosal) having spread via lymph nodes to other organs; predominantly the bones, liver, lungs and brain. ACT of tumour-infiltrating lymphocytes (TILs) concurrently with interleukin-2 into MM patients can stimulate tumour regression. Some studies claimed 34% respond whereas others suggest 50% have clinical response. As illustrated in Figure 3, TILs are attained by developing single-cell suspensions from tumour. This is followed by culturing these cells with interleukin-2 to activate T-cell expansion. After 6-8 weeks, there should be sufficient numbers for adoptive transfer. Studies have shown that TILs’ ability to localize tumour is directly proportional with clinical response. This emphasises that although ACT can synthesize toxicities, there is potential benefit for augmenting immune response as it induces remission in advanced cancer.Epstein–Barr virus (EBV)-related lymphoma is another example of where Adoptive T-cell transfer was successful post-BMT. Additionally, many methods are being investigated to improve Adoptive T-cell therapy such as transferring of tumour-specific T-cell receptor (TCR) genes into other T-cells and have shown to transmit specificity. This will enhance avidity to particular tumour antigens, less labour-intensive, reduce time and cost.

Besides targeted-immunotherapy there are non-specific approaches that are being developed to augment immune response such as cytokines and checkpoint inhibitors shown in Figure 4. Cytokines induces a general anti-tumour immune response by two approaches: interrelate directly with tumour cells to stop growth or die. For example, interleukin-2 therapy causes complete response that can be durable in 4-6% of patients with melanoma and renal cell carcinoma. The second approach is via an indirect mechanism.

Conversely, some cytokines have side-effects such as interleukin-6 whereby it stops growth of several tumours but encourage growth of others. Additionally, despite cytokines are effective when administered alone. A combination of different cytokines infused causes a synergistic effect generating a more potent anti-cancer agent. Recently, a new therapy has been designed for malignant breast cancer patients with elevated hPRL levels. G129R-IL2 protein, composed of human prolactin (hPRL) endocrine antagonist G129RR and interleukin-2, can avoid signal transduction mediated by hPRL to stimulate T-lymphocytes near location of tumours. There is hope that G129R-IL2 protein will play a significant role towards breast cancer treatment.

Moreover, checkpoints such as PD-1 protect normal cells from immune hyper-activation when up-regulated in some tumours that suppress T-cell function allowing tumour cells to avoid immune system. Thus, suppressing a checkpoint could increase anti-tumour T-cell response. Recently, checkpoint kinase (CHK) inhibitors such as 1 and 2 were designed and have shown efficacy when alone and in combination with conventional therapies by preventing DNA damage response. However, findings from early phase clinical trials have been varied and CHK-2 therapeutic context is indistinguishable. Thus, further investigations is necessary.

Ultimately, the future of cancer immunotherapy holds promise, with many technologies being developed to augment immune response.This has overlapped with improvements in techniques behind these technologies that brought them to success. Amongst these include humanization of MAbs, genetic engineering and Hybridoma technology. Potentially immunotherapies will be a therapeutic option for cancer besides conventional therapies and this would raise possibility of durable remissions for patients

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Hafsa Waseela is in the medical field and is continuing to pursue her studies to reach her ultimate vocation to become a Lecturer specialising in Oncology and Cancer. She is an artist, poet and is an active member of a number of dawah organisations, community associations and charities in the UK and abroad. To read more of her works, please visit her website www.hafsaabbas.com

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