Panel Discussion Summary
The discussion about bispecific T Cell Engagers built upon the talks from the virtual event, focusing on the current challenges of T cell engager antibodies as cancer therapeutics. Silvia Hnatova details the key points raised in the discussion, featuring:
Dr Katherine Harris, Senior Director of Discovery at TenoBio
Dr Alison Crawford, Senior Staff Scientist, Oncology and Angiogenesis at Regeneron Pharmaceuticals
Prof Paul Parren, EVP, Head of R&D and Professor at Lava Therapeutics and Leiden University
Dr Teemu Junttila, Principal Scientist, Translational Oncology at Genentech
Dr Hans van der Vliet, Chief Scientific Officer at Lava Therapeutics BV
Dr Brian Avanzino, Scientist III, Discovery at TeneoBio
Dr Katherine Harris opened the discussion highlighting that currently, there is only one therapeutic T cell engager bispecific antibody approved (blinatumomab targetting CD19 and CD3). However, this drug has serious side effects including cytotoxicity. Dr Harris underlined the importance of an improved safety profile in developing next-generation bispecific T cell engagers. She then opened the forum for discussion on cytokine release syndrome (CRS).
Dr Alison Crawford agreed that toxicity and efficacy in solid tumours are major challenges for bispecific T cell engagers. She pointed out that our knowledge about the mechanism CRS is incomplete and that current clinical trials are hindered by initial CRS response. Dr Crawford highlighted that it is not yet understood why step-up dosing of bispecific antibodies works and for how long.
Prof Paul Parren, Dr Crawford and Dr Teemu Junttila built upon this by discussing the detection of different cytokines during CRS. Dr Junttila suggested that perhaps de-sensitisation could be taking place and CRS could be a result of the quickly escalating cytokine response in patients. He pointed out that further understanding of CRS would be needed for clinical use.
Prof Parren asked Dr Hans van der Vliet whether reduced toxicity could be achieved by reducing affinity to targets. Dr van der Vliet explained that there are T cell subsets are involved in CRS. He said that T cell subsets could be triggered instantaneously, and have the “potential to have a different effect on the cytokine spike”. Dr van der Vliet pointed out that the size of the cell population makes a difference and different T cell subsets produce different cytokines – allowing specific targetting. He hypothesised that this could improve the safety profile.
There was a further discussion about specific cytokine targetting and liver toxicity, supported by data from Dr Crawford’s lab. Dr Brian Avanzino asked if such specific cytokine targetting could drive selection pressure for tumour antigen loss. Dr Crawford confirmed that antigen-negative relapse following CRS remains the main problem with anti-CD3 bispecifics.
Prof Parren answered a question from the audience about whether “any T cell targets beyond CD3 to engage T cells would be possible in TME without systemic effects”. Dr van der Vliet elaborated on this question highlighting gamma-delta T cells that have a limited cytokine profile. He explained that the cell subset targetting would not have to be limited to T cells, giving examples of NK cells, in addition to pointing to his research on gamma-delta cells and their cytokine release. Dr van der Vliet concluded that there is not sufficient clinical data to answer the question of cell subset targetting at this time.
Dr Crawford suggested that mitigating systemic response to prevent CRS could prove more useful than targeting of T cell subsets, due to the need for engaging as many T cells as possible in big tumours. Dr Junttila agreed that efficacy of bispecifics in solid tumours is a more pressing issue than the toxicity, adding that we can ‘find a creative way of using the antibodies’, but they need to work.
Prof Parren switched gears, asking Dr van der Vliet if we could treat tumours that have high levels of gamma-delta T cells or we could recruit those cells to the tumour. Prof Vliet added that there is evidence to suggest that the number of infiltrating gamma-delta T cells in different tumours differs.
He said that in his research, he did not see a lower limit for gamma-delta T cell numbers that would be needed to trigger a response, unless none present. He said we might want to implement a lower limit for gamma-delta T cell numbers later, once more is known about this cell subpopulation.
Dr Crawford elaborated on her statement that ‘the larger the tumour, the more difficult to treat’. She explained that this is dependent on the size of the tumour vs T cell ratio. In her preclinical mouse models, she saw that a much bigger number of T cells is needed when tumours are too big in size (above 200mm) and they reach exponential growth, worsening the prognosis.
Dr Avanzino and Dr Crawford discussed targeting of different cytokines, especially those secreted at different times. Dr Harris added that on-target/off-tumour toxicity is an issue and asked the panel about strategies to mitigate the toxicity. Dr Crawford suggested that affinity and checkpoints would be important to be taken into account to decrease toxicity in solid tumour targets.
There was a brief discussion about the relevance of animal models when studying bispecific antibodies. Dr Crawford talked about the xenogenic models she uses in her lab and humanized mouse models.
Humanized mouse models are very useful for studying potentially clinically relevant targets, she said, agreeing with Dr Junttila that mouse immune response is not always reflective of a human immune response. It was agreed that questions should be selected carefully to enable the best use of animal models.
The last question was asked by Dr Avanzino to Dr Crawford’s whether mouse models are reflective of potential toxicity in humans. Dr Crawford highlighted the importance of ‘choosing the right question’ and the right model for addressing toxicity.
She emphasised the need for ‘the target expressed in the same place at the same level’. The discussion was concluded by everyone agreeing that despite unresolved challenges, it was an exciting time for bispecific antibodies and rapid advancement on the horizon.
