Speaking at Amgen One, Associate Professor Simon Harrison, Lead for the CAR T-cell Clinical Program at the Peter MacCallum Cancer Centre gave delegates an update on chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers (BiTEs) for multiple myeloma (MM).

“Given the myeloma microenvironment is highly immunoactive, redirecting T-cells to fight the patient’s own cancer has been a vision for some time now.^1,2 We might still be a little way off widespread use, as there’s still work to be done to understand how best to utilise them,” he began.

Piece by piece, we’re learning more about how to optimise BiTEs for MM

BiTEs are generated by genetically linking a single chain variable fragment (scFv) of monoclonal antibodies (mAbs) for CD3 on T-cells and the target antigen on a tumour cell.² The two separate, single chain peptides are held together by a flexible linker.³ “When they connect the T-cell to the myeloma cell, a synapse between the two is formed which activates the T-cell. This leads to upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines which results in redirected lysis of target cells.³ Handily, there’s also a proliferative effect as well, with expansion of polyclonal T-cells,”⁴ he explained.

“The theory is nice,” explained Assoc/Prof. Harrison, “but when first developed the canonical BiTE molecule had a relatively short half-life of around one to four hours in vivo, which means continuous infusion is required. By adding on a half-life extender (HLE) domain it’s been possible to extend the in vivo half life to about seven days, which is a more convenient weekly infusion option for patients.”^5,6

In the MM landscape, there are a few BiTE molecules in clinical development, including AMG 420, an anti-BCMA BiTE with Phase I results in relapsed/refractory MM after ≥2 prior treatment lines.⁷ Another is AMG 701 a BCMA-targeting HLE BiTE which is currently recruiting for its first in-human study, again in relapsed/refractory MM after an immunomodulatory drug, proteasome inhibitor and where approved and available, a CD38-directed cytolytic antibody.⁷ “Then there’s those targeting FcRH5 and CD3 such as BFCR4350A, and AMG 424, which targets CD3/CD38 currently in Phase I trials,”⁷ Assoc/Prof. Harrison noted.

Getting a ‘Google Earth’ view of CAR T-cells in action is now possible

Reflecting on the trial results of BCMA-targeting CAR T-cell therapies like LCAR-B38M and bb2121, Assoc/Prof. Harrison emphasised “while there’s been impressive response rates, there’s more to be understood about how we utilise these therapies in patients.⁸ Some patients achieve minimal residual disease (MRD) negativity with these therapies, others do not. We’ve also seen that even those who do [achieve MRD negativity] still eventually relapse.⁸ Will we need to use multiple CAR T-cell therapies? When you look at the reasons for failure, that is antigen loss variants, failure of persistence, T-cell exhaustion or failure of trafficking, we realise there’s more to be done yet. Some of the new tools include In-labelled T-cells and positron emission tomography (PET) magnetic resonance imaging (MRI) that enable us to see the cells traffic to the bone marrow and monitor responses even more closely than before.⁹ This makes it an exciting time indeed. We now wait to see what unfolds.”

This article was sponsored by Amgen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.

References:

1. Stakiw J, et al. Tumor Microenviron 2018;1(1):1-8.
2. Rodriguez-Otero P, et al. Haematologica 2017;102(3):423-432.
3. Wolf E, et al. Drug Discov Today 2005;10(18):1237-1244.
4. Bargou R, et al. Science 2008;321:974-977.
5. Lorenczeweski G, et al. Blood 2017;130:2815.
6. Goyos A, et al. Blood 2017;130:5389.
7. U.S. National Library of Medicine. ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov (accessed 28 February 2019).
8. Zhao W-H, et al. 955 Updated analysis of a phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B-cell maturation antigen, in patients with relapsed/refractory multiple myeloma. Presented at the American Society for Hematology, December 3 2019.
9. Davenport AJ, et al. Cancer Immunol Res 2015;3(5):483-494.