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The advance of immunotherapy in oncology treatment

Immunotherapy was one of the main topics at this year’s ASCO Annual Meeting in Chicago, US. The recently-launched Cancer Trials Ireland (formerly ICORG) held its own meeting on immunotherapy in Dublin at the end of June. The meeting focused on new developments in the area, which is revolutionising the treatment of cancer patients.

The first speaker, Dr Joanne Lysaght, Assistant Professor and Principal Investigator in Translational Oncology at Trinity College Dublin (TCD), provided an overview about how immunotherapy has transformed the landscape of cancer treatment. Dr Lysaght gave examples of new treatments such as atezolizumab, which targets the PD-L1 pathway and was recently approved by the US FDA, and relevant companion diagnostics. According to Dr Lysaght, the field of immunotherapy is constantly evolving and new targets are being identified all the time. She said that future targets for immune checkpoint inhibitors include blocking inhibitory receptors TIM-3, BTLA, and LAG3, and stimulating activating receptors CD28, CD27, CD40, and 4-1BB. She also gave examples of the latest immunotherapy breakthroughs other than immune checkpoint inhibitors, such as oncolytic viruses.

These viruses cannot replicate in healthy cells. However, they replicate in malignant cells, releasing GM-CSF and antigens to stimulate immune cells to counteract the cancer. One of these therapies, the oncolytic virus talimogene laherparepvec, was approved by the FDA in the US in October 2015. Another promising area within immunotherapy is chimeric antigen receptors (CAR) T-cells, to which the FDA recently granted ‘breakthrough therapy’ designation. CAR T-cell therapies work by genetically engineering a patient’s own T-cells to produce what are called chimeric antigen receptors that are able to stick to tumour cells based on the presence of certain proteins.

Many CAR T-cell therapies being developed today specifically target the CD19 (cluster of differentiation 19) antigen, as it is found on the surface of most B-cells, making it an attractive target for therapies to treat various B-cell lymphomas.

The FDA also recently announced that it wants to create two new databases that will allow it to look at safety and manufacturing information across multiple applications for these therapies.

Dr Lysaght also referred to bispecific T-cell engager antibodies. These are derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1. One of the drugs in this class of therapy, blinatumomab, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL.

Benefits of clinical trials

Dr Lysaght also stressed the importance of patients being involved in clinical trials in order to obtain further evidence of the benefits of immunotherapy for cancer patients from a translational research perspective. She said clinical trials provide the access to sample acquisition and clinical data from each stage of the patient treatment pathway. They also provide the opportunity to assess observations made in preclinical models in human ex vivo tissues, and provide controlled environments in a relatively homogenous population.

“Clinical trials do not have to be immunotherapy-focused but important immunological questions can be answered as part of secondary objectives/endpoints,” Dr Lysaght said. “Samples can be obtained with ethics and consent from non-trial patients.”

Other benefits include providing the opportunity for acquiring new international cohorts for validation and to develop new national and international collaborators and contacts.

Dr Lysaght also made recommendations on how to progress translational cancer immunology research. For example, she highlighted, for the purposes of research, how laboratory mice resemble newborn humans, not adults, as they lack effector-differentiated and mucosally-distributed memory T-cells. She pointed to recent research showing “dirty” (feral) mice might be more valuable for investigating diseases that involve the immune or inflammatory system, including cancer.

“Such mice would increase translational potential to human disease and inform the efficacy of preclinical prophylactic and therapeutic modalities,” she said.

Dr Lysaght maintained that researchers need to be involved at the design stage of clinical trials to ensure the most is made of precious samples (most appropriate sample types/timepoints).

She also spoke of the need to develop consolidated centres of excellence for research in oncology and immuno-oncology, and to integrate immunologists as standard into clinical cancer trials.

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Pictured (L to R): Dr Grace Foley, Pfizer;  DrJerome Coffey, Director, National Cancer Control Programme; Dr Siobhan Mitchell, Medical Director, BMS; Ms Eibhlin Mulroe, CEO, Cancer Trials Ireland; Ms Kay Curtin, Melanoma Ireland; Prof Seamus O’Reilly, Cork University Hospital; Dr Joanne Lysaght, TCD; Mr Cathal O’Ceallaigh, MSD; and Ms Susan Graham, Celgene


Biobanks

Biobanks are another significant issue, according to the TCD researcher. She said that biobanks should be preferably housed on hospital campuses, that dedicated staff to acquire, process and manage the biobanks should be supported, and that all biobanks should have a data manager to ensure all samples are linked with full clinical data. Dr Lysaght argued that extra funding for biobanking staff is necessary. There is also the need for strict protocols for tissue processing and storage, as well as careful governance of tissues and data to ensure compliance with standards, ethics, patient consent and data protection.

She added that currently, there are a lot of individually-run biobanks in standalone departments with no funding or quality assurance provided.

Dr Lysaght presented a list of what, for her, were the key areas for immunotherapy research. The first was assessing the suitability of currently-approved immunotherapy in multiple cancer types. The next was the importance of determining the sequence of treatment and whether immunotherapy should be administered before or after surgery, chemotherapy/and or radiotherapy.

Regarding dosing, she said that low doses of radiotherapy are not very immunogenic and that higher doses release danger signals and activate innate immune responses.

Combination therapy is a promising area of research, according to Dr Lysaght, with emphasis being placed on identifying the most efficacious combination of chemotherapy and radiation.

She warned that there is a need for clinicians and researchers to think more about resistance to immunotherapies. Naturally-occurring and therapy-induced acquired resistance is becoming more noticeable as immunotherapy becomes part of the standard of care.

Dr Lysaght said it was important to develop strategies to monitor and overcome resistance and identify why a “substantial” number of patients still derive no or limited benefit from immunotherapies, despite the advances made in the area.

“It is a hugely exciting time but many challenges remain for cancer immunotherapy research,” she said, stating that Ireland is a world leader in immunology and cancer research but that there is a need to harness all of the expertise in the country. Dr Lysaght said that it is currently very difficult to identify researchers working in immunotherapy creation, which is a “major hurdle” for industry engagement and collaborations both nationally and internationally.

The meeting also featured talks from representatives of the pharmaceutical industry (BMS, Pfizer, Celgene and MSD), who all spoke about the benefits of immunotherapy and new drugs in their pipelines.

Cancer strategy

The Director of the National Cancer Control Programme, Prof Jerome Coffey, also spoke at the meeting. He said that the evidence on using immunotherapy to treat many cancers is growing, pointing to trials in breast, brain, myeloma, colorectal, ovarian and haematological malignancies. During his talk, Prof Coffey provided details about the eagerly-anticipated new National Cancer Strategy, which is due to be published in the near future.

“It is road map for the next 10 years,” he said. “Like all good strategies, it will talk about manpower, planning, resources and all the rest of it, but the specific challenge in cancer is that we know what the growth in incidence curves is, we know that for the incidence you can multiply that by four to get the prevalence numbers and those patients need healthcare, and we know that is getting more complex. We know that there are gaps in staffing, we know that quite apart from treatment, there are huge advances in molecular diagnostics, somatic and germinal mutation testing and personalised medicine.”

Prof Coffey also underlined how the new strategy will put a greater emphasis on research than the previous strategies.

“I think for today’s talk, the real issue is that research is now not an optional extra,” he said.

“It became very clear at the steering group and the cancer strategy discussions that research activities are an essential part of a designated cancer centre, and those staff have to be permanent staff and it is not just clinical staff; a lot of the clinical work is done pro bono by doctors but you need permanent research staff to support that. You need administrative support, you need technology, you need infrastructure and space in the centres to make it happen. My preference is that there would be a criteria for classifying centres as designated cancer centres, so it becomes a quality standard right across the board. It makes it sustainable, it makes it a permanent activity and then it builds into earlier and earlier stages of training and education for all healthcare professionals.”

Prof Coffey also stated that there is the potential for changing the manner in which clinical trials are approached internationally.

“The clinical trial design historically has been big, phase 3 trials, hundreds and thousands of patients across many countries,” he explained. “It will take years to design and run and years before you get outcomes. Looking at overall survival advantages, it may be that now is a time to talk about change to progression-free survival.”

Outside the cancer strategy, future directions in immunotherapy will be the development of new treatments and the sequencing of these treatments, according to Prof Coffey.

It is also important to examine why some patients respond and others with the same tumour types do not.

“The question for me really is that these drugs have higher response rates than cytotoxics but why they are not 100 per cent [effective] and why the duration response, although much better, is not much longer,” he said in conclusion. “What are the mechanisms for resistance? These are questions that will be answered. It is just a fascinating area and it is a great time to be involved.”

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