Cancer Immunotherapy – The Next Scientific Breakthrough

 

The month of "June" is identified as Cancer Immunotherapy Research Awareness Month. This year (2023) marks a decade since cancer immunotherapy gained its first acknowledgment as a notable "breakthrough of the year" by science magazine in 2013.

According to studies, more than thirty cancer types are treatable with immunotherapy, and the objective of this awareness month is to expand this figure and provide life-saving treatments to more individuals dealing with cancer.

How is Cancer Targeted by Immunotherapy?

Conventional approaches by a clinical research organization to combat cancer, such as radiation therapy and chemotherapy tend to bring about distressing physical and emotional repercussions. Unfortunately, their efficacy in treating metastatic cancers is restrained frequently. Furthermore, these treatment methods seldom lead to a permanent solution as patients may experience relapses or develop resistance to the treatment.

Immunotherapy presents a promising avenue for eradicating cancer by empowering the patient's immune system to identify and combat cancer cells. By embracing a fresh perspective from several health research institutes, this method has proven to enhance the survival rates of cancers that exhibit unfavorable clinical outcomes through conventional means, such as metastatic melanoma or pancreatic ductal adenocarcinoma.

An additional advantage of immunotherapies lies in their potential to attain sustained remission, as the immune system can detect recurring cancer cells, thereby offering long-lasting and possibly everlasting safeguards against this debilitating disease.

Different Types Of immunotherapies

Presently, there exists a multitude of immunotherapy options available to combat the spread of cancer. These include the following:

1. Immune Checkpoint Inhibitors: These interventions obstruct immune checkpoints that malignancies exploit to elude the body's natural defense system.

2. Immunomodulators: By stimulating the body's immune response, these substances empower the immune system to combat cancer effectively. Cytokines, adjuvants, and agonists are some examples of immunomodulators employed in cancer treatment.

3. Adoptive Cell Therapy: This approach involves isolating immune cells from the patient and modifying or expanding a specific cell population to recognize cancer antigens. Notable adoptive cell therapies encompass CAR-T therapy, tumor-infiltrating lymphocytes (TIL) therapy, engineered T-cell receptor therapy, and natural killer (NK) cell therapy.

4. Targeted Antibodies: Utilizing monoclonal antibodies that target cancer-specific antigens specifically, these therapies prove effective in combating cancer. Monospecific, bispecific, or cytotoxic drug-conjugated antibodies are utilized in this regard.

5. Oncolytic Virus Therapy presents a ray of hope in the realm of cancer treatment as it involves the strategic alteration of a virus to specifically target and annihilate cancer cells while leaving healthy cells unharmed. This innovative approach has garnered recognition from the esteemed US Food and Drug Administration (FDA), granting approval for IMLYGIC, a modified herpes virus with the remarkable ability to obliterate metastatic melanoma cells upon direct injection into the tumor.

6. Cancer Vaccines: These vaccines serve the purpose of training the immune system to recognize existing cancers or prevent cancer caused by viral infections. FDA-approved vaccines exist for the prevention of cervical and liver cancer and the treatment of prostate cancer, metastatic melanoma, and early-stage bladder cancer.

As our understanding of T cells and various other immune cell behaviors and interactions with cancer cells expands, the list of immunotherapy types and specific therapeutic options continues to grow.

Current Trends in Cancer Immunotherapy Research

Checkpoint Inhibitors

Lately, there has been an increased focus on checkpoint inhibitors, which garnered significant attention when Dr. James Allison and Dr. Tasuku Honjo were awarded the prestigious 2018 Nobel Prize. These brilliant minds at health research institutes uncovered the remarkable manner cancer cells exploit CTLA-4 and PD-1 to evade the immune system.

It's worth noting that the mechanism of action for these two molecules differs substantially. While CTLA-4 is a molecule that suppresses the immune response and is typically employed to ensure it remains under control, limiting T-cell priming through competition with the costimulatory molecule CD28, PD-1 operates differently.

In 2011, the FDA approved the first-ever checkpoint inhibitor, Ipilimumab. It specifically targets and inhibits CTLA-4. This inhibition enables T cells to respond to tumour antigens.

In contrast, primed T cells express PD-1, which serves as a suppressor of T-cell function when it engages with PD-L1 found on tumour cells and myeloid cells within the tumour microenvironment (TME).

The dynamic duo of pembrolizumab and nivolumab work their magic by obstructing the PD-1 and PD-L1 interaction within the TME and the tumour itself, thus reviving the weary T cells and reinstating their optimal performance.

Highlighting the limited efficacy of checkpoint inhibitors in cancer treatment, researchers and medical professionals have worked to identify methods for increasing effectiveness and safety.

As a case in point, the FDA approved the combination of PD-1 inhibitor nivolumab with CTLA-4 inhibitor ipilimumab to treat metastatic non-small cell lung cancer (NSCLC). Recently, the agency has also allowed the use of relatlimab - an inhibitor of the immune checkpoint LAG3 - together with nivolumab for treating unresectable or metastatic melanoma.

Targeted Antibody Immunotherapy

Targeted antibodies possess the ability to obstruct the function of specific molecules, trigger programmed cell death, or regulate signalling pathways. As an illustration, when the monoclonal antibody known as Herceptin latches onto excessively expressed HER2 receptors found in breast and stomach cancers, it mitigates the activity of downstream signalling pathways, thereby instigating apoptosis and halting the growth of cells. Since approximately 25% of breast cancers exhibit HER2 positivity, Herceptin serves as a formidable weapon in the existing arsenal of cancer therapies. Although Herceptin has obtained approval since 1998, researchers persist in exploring avenues to enhance its efficacy or reduce its toxicity by investigating alternative epitopes or modifying the antibody to enhance its affinity.

Furthermore, the antibody can be joined with a chemotherapy payload, creating an antibody-drug conjugate that selectively targets the cytotoxic molecule in the tumour. Lastly, bispecific antibodies represent an innovative approach that merges the variable regions of two distinct antibodies into a single molecule, enabling it to recognize epitopes from, for instance, both a cancer cell and a T cell. By doing so, the bispecific antibody brings the T cell into close proximity to the tumour, resulting in T cell activation, proliferation, and T cell-mediated elimination of cancer cells. The first bispecific antibody, blinatumomab, received FDA approval in 2014 for the treatment of leukaemia patients.

Immunotherapies, particularly utilizing IgG and T cells to help fortify the immune system, have produced promising outcomes. However, research into more immune cells and immunoglobulins is being conducted. One of the possibilities being studied entails immunoglobulin E (IgE) to fight chondroitin sulfate proteoglycan 4 (CSPG4), which can be present in up to 70% of melanomas. IgE is activated in response to allergens such as pollen, and it has certain advantages over IgG therapies. These include its increased affinity for FceRI receptors, lack of inhibitory receptors for IgE, capacity to bring about a response with various effector cells in comparison to IgG, low level of existence in the blood with little opposition for receptor binding, and its capability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) without having to depend on complement-mediated cytotoxicity (CDC).

Adoptive Cell Therapy

Individualized medicine has several faces, and one of them is adoptive cell therapy. In this technique, cells taken from the patient or donor are modified so that they become proficient in detecting and destroying tumours - referred to as 'living drugs'. Notable methods of adoptive cell therapy include tumour-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy. After changing the cells, they are injected back into the individual.

Extracting TILs from tumour biopsies that can identify multiple cancer antigens, then multiplying their numbers and administering them to the patient, has demonstrated immense potential as a viable and secure combination with chemotherapy and IL-2, in treating melanoma and other solid tumours. Nevertheless, the presence of signals in the tumour microenvironment typically dampens the activity of these blood cells.

Due to the difficulty in cultivating enough TILs and the reality that not all patients have months to wait, alternative approaches are being investigated. For instance, combining TILs with checkpoint inhibitors and the development of an engineered TIL with the FDA's approval, which eliminates the need for IL-2, are among the possible solutions to expand the reach of this promising therapy.

CAR-T cell therapy has established itself as a preeminent form of adoptive cell therapy due to its propensity for potent response rates and long-lasting remission when battling aggressive leukemias and lymphomas. This procedure entails harvesting and engineering immune cells from the patient, enabling them to recognize tumour antigens, thereby inducing tumour cell destruction. The United States Food and Drug Administration has approved six CAR-T treatments that target acute lymphoblastic leukaemia in children, B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma in adults.

Despite the potential of CAR-T therapies, progression towards treating solid tumours is still lagging. These roadblocks include difficulty recognizing tumour-specific antigens, the TME's ability to stymie immunotherapy, and the attendant toxicities associated with the CAR-T cells. In response to these limitations, significant efforts are being made to circumvent the immunosuppressive power of the TME, for example by combining CAR-T cell treatments with checkpoint inhibitor drugs, or by developing CARs capable of disregarding immunosuppressive cues.

The CAR-T process requires the isolation of T cells, engineering to produce CAR, and validating surface expression. However, detection reagents with the correct specificity can be hard to acquire. An alternative method is to validate the CAR-T independently of antigens using antibodies that target the linker sequence on the scFv between the variable heavy and light domains.

Cancer Vaccines

Driven by the immediate necessity of a COVID-19 vaccine, advances made by clinical research organizations, in tandem with an improved grasp of the immune system, have now been used to craft cancer vaccines. An initially encouraging therapeutic plan that was mostly disregarded during the 2010s, vaccines that stimulate an immune response to battle castration-resistant prostate cancer and dangerous non-muscle-invasive bladder cancer (NMIBC) have been accepted by the Food and Drug Administration.

With the invention of nucleic acid vaccines, difficulties related to manufacturing time and administering live-attenuated vaccines to immunocompromised individuals have been addressed by health research institutes. Notably, the human papillomavirus (HPV) vaccine has been developed to protect against cervical cancers and hepatitis B virus vaccines for liver cancer. Unfortunately, preventative vaccines for non-viral cancers are not currently available in the clinic. However, researchers are studying whether improved diagnostic and screening procedures can be coupled with therapeutic vaccines to stimulate anti-cancer immunity before cancer progresses to a more advanced stage.

Oncology Research – A Promising Future

Immunotherapy has been a ray of hope for cancer patients, thus providing them some of the most novel treatments. However, it is not a panacea. Joining forces with tried-and-true strategies such as surgery, chemotherapy, and radiotherapy can help medical experts craft tailored treatments for every patient.

Constant novel developments in science are being discovered. As a recent example, researchers have been exploring the impact of gut microbiome tuning on patient response to treatments. An experiment with mice found that microbiota sourced from cancer patients had an influence on PD-L2 and RGMb protein expression and improved the responsiveness to anti-PD-1 immunotherapy. Conversely, a broad spectrum of antibiotics reduced the same response. These results hint at the potential of improving patient responses to immunotherapy through manipulation of the gut microbiome.

Thanks to immunotherapies, cancer treatments have been revolutionized, and physicians have an extensive range of options to select from.

As we continue to gain an understanding of the immune system from studies conducted by clinical research organizations and design novel approaches to manipulate regulatory systems, the array of solutions will increase, inching us closer to a future in which we can ward off and even heal metastatic cancer.

About I3T

In January 2020, Johns Hopkins University, Baltimore, Maryland, in the United States became a collaborating partner of the International Institute of Innovation & Technology Kolkata, India (I3TK). It has a 156,000 square feet state-of-the-art building. It was developed with a specific goal to research and educate public health-related subjects. As such, I3T has an Advanced Diagnostic Centre focusing on the exploration of methods for cancer prevention, detection, and improvement of patient quality of life through clinical trials.