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Opportunities and challenges for sub-cutaneous PD-1/L1 inhibitors: KOL perspective

2 August 2021

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ESMO TAT 2021

KEY TAKEAWAYS

Despite the difficulties of a global pandemic, new approaches for the improved treatment of cancer proceed with pace.

Two of our director team recently attended the ESMO TAT 2021 meeting which showcased the new developments entering clinical testing.

“This year’s ESMO TAT highlighted the continued interest in, and commitment to, further develop immunological approaches and extend the benefit to more patients. There are a number of potential game changers if they were to be successful, however, first, significant challenges to be overcome.”

Siobhan Davies

Here we share some key highlights:

Efforts to make CAR-T in solid tumors a reality 1 continue despite significant challenges

Developing CAR-T for solid tumors is a formidable task associated with numerous additional challenges e.g. antigen heterogeneity, suboptimal migration, tumor matrix and stroma and the immunosuppressive tumor environment. Because CAR-T have the potential for profound and rapid efficacy and even cure in some instances, efforts continue.

Future mechanisms to armour CAR-T that were discussed at the meeting involve blocking co-inhibitory receptors, preventing immune exhaustion, promoting the secretion of cytokines (e.g. IL-18) or building in resistance to immunosuppressive cytokines, as is the case with PSMA-dnTGFβR2 CAR-T which is currently in Phase I development (Tmunity Therapeutics) for metastatic castrate-resistant prostate cancer.

The BiTE® / T-cell bispecific universe is expanding with advancements in molecular structure, novel targets and combination approaches

Bispecific T-cell engagers (BiTEs®) and other T-cell redirecting bispecific antibody and protein approaches have attracted a lot of interest offering the potential to bring T-cell innovation to more patients; through their versatility to target a number of tumor associated antigens, and their ‘off-the-shelf’ design meaning they are lower cost and faster and simpler to deliver compared with CAR-T. Molecules are being designed with dosing (e.g. silent Fc fragments to remove the need for continuous intravenous administration) and toxicity, namely cytokine release syndrome, in mind. For example, IGM Biosciences’ IGM2323, a IgM based T-cell engager, has 10 CD20 binding sites to 1 CD3 binding site and this, along with its larger size vs. IgG, provides more physiological T-cell activation.

A wide range of potential targets and strategies are being explored that may provide opportunities to extend the benefit of checkpoint inhibitors

Mechanisms that build on current checkpoint inhibitors, or help overcome resistance, are a continued focus; with a number of potential targets in immune system activation and recruitment, a wide range of research approaches are being pursued. 10+ sessions within the 2-day meeting described opportunities to extend the offering of current checkpoint inhibitors.

These ranged from advancing known concepts (e.g. next generation CTLA-4 approaches designed to optimise the risk-benefit profile e.g. using Probody technology® or a nonfucosylated approach), to novel strategies e.g. leveraging the microbiome, and ‘bug drugs’ as IO boosters with new clinical data on fecal microbiota transplantation and bacterial therapeutics (e.g. MET4) as mechanisms to overcome resistance. Additionally, attention is being given to developing targets which may have been unsuccessful to date e.g. combining OX-40, which as a monotherapy has not delivered the clinical benefit expected, with vaccines or MEK inhibitors. Last year UbiVac and BMS initiated a phase I trial for advanced triple negative Breast Cancer using the triple combination DPV-001, anti- OX40 (BMS-986178) and nivolumab.

What does this mean forthe future landscape?

  • Whether CAR-T will become a reality insolid tumor is yet to be seen. However, to become commercially viable for a wider share of patients, “off-the-shelf” allogenic CAR- treatments including CAR-Ts, currently in clinical development, will likely be needed to allow speedier delivery, and avoid the logistical challenges and subsequent high costs currently associated with CAR-T treatment.
  • Bi-specific T-cell antibody constructs offer huge potential and could prove highly competitive for CAR-T therapies, especially before the availability of allogenic CAR-Ts. However, it is yet to be seen how response rates will compare and whether response rates will reflect CAR-T efficacy at lower antigen density. It is also possible that T-cell engagers could reignite exhausted CAR-T at later time points, so a detailed understanding of the best combinations and treatment sequencing will be key.
  • Beyond CAR-T and T-cell engagers, there are a number of approaches / mechanisms that may augment response to checkpoint inhibitors. The wealth of research reflects the huge unmet need in this area; but a number of therapies in late stage development, including anti-LAG-3 and anti-TIGIT monoclonal antibodies, may shape the opportunity.

To discuss your oncology needs further please reach out to Siobhan Davies s.davies@blueprintpartnership.com or Mike Pepp m.pepp@blueprintpartnership.com