From the PR: ''The data we presented today continue to illustrate the differentiated profile of our cNeT product and overall platform that builds on standard TIL therapy by leveraging clonal neoantigen targeting to deliver a more precise and potent product,'' said Dr Iraj Ali, Chief Executive Officer of Achilles. ''The ability to reliably detect and quantify our active component is a key differentiator of our world-class technology that is unique in the field and which we believe will be critical for the successful development of TIL-based therapies.''
Engraftment Kinetics, Quantification and Tracking of cNeT in CHIRON and THETIS
Data presented from the first eight patients dosed across the first-in-human PI/IIa CHIRON and THETIS trials confirm the ability of Achilles' VELOS manufacturing process to generate fit, polyclonal cNeT that can target multiple cancer neoantigens present on all tumour cells. Achilles' platform can detect, quantify and track the patient-specific cNeT during manufacturing and post patient administration, allowing for extensive product characterization and immune-monitoring.
At the data cut-off for this presentation, five patients with melanoma (THETIS) and three patients with NSCLC (CHIRON) had received their cNeT infusion. The median age of the cohort was 57 years and patients had received a median of 2.5 lines of prior therapy. 88% (7 of 8) of the cNeT products dosed targeted multiple clonal neoantigens present on all tumor cells. In these seven products, the number of individual reactivities ranged from two to twenty-eight and cNeT were detected in the blood of 71% (5 of 7) of the patients following infusion at time points up to six weeks post dosing. Best response in the eight dosed patients was stable disease in 63% (5 of 8) in this initial, low-dose cohort generated using VELOS Process 1. The tolerability profile was generally similar to that of standard TIL products that have not been enriched for cNeT reactivity, with none of the higher-grade adverse events more commonly associated with the use of higher doses of interleukin-2 (IL-2). There were no suspected unexpected serious adverse reactions reported since the previous update on the first six patients earlier in 2021. Overall, in the cohort there were three events of cytokine release syndrome and one ICANS event deemed to be possibly related to cNeT treatment. A previously disclosed case of encephalopathy was subsequently deemed unlikely related to cNeT treatment following an Independent Data Safety Monitoring Committee review.
''The encouraging data from this low-dose cohort are important as they show how the Achilles platform can answer potency questions, gives a first look at mechanism of action in a TIL product, and adds confidence to now move to higher cell doses,'' said Dr Samra Turajlic, THETIS Chief Investigator, Royal Marsden NHS Foundation Trust, London, UK. ''I look forward to exploring higher median doses from VELOS Process 2 manufacturing that should more predictably be in the anticipated therapeutic range, based on work done with other cell therapies. As we move to higher cNeT doses I expect improved cellular engraftment, both in terms of peak expansion and durability, and hope to see greater evidence of anti-tumour activity.''
The median cNeT dose in patients in this low-dose, Process 1 cohort was 14.2 million cNeT, which is in line with previous updates. VELOS Process 1 manufacturing generated doses between 0.1 million and 287 million cNeT. cNeT reactivity, defined as the percentage of clonal neoantigen-reactive cells in the final dosed products, ranged from 5% to 77%. As the dataset expands and matures, these metrics of detection and expansion will be correlated with product, clinical and genomic characteristics to determine variables associated with peripheral cNeT dynamics and clinical response.
VELOS™ Process 2 Manufacturing
Achilles' VELOS Process 2 manufacturing generated an 18-fold increase in cNeT compared to Process 1 in this proof-of-concept study. The increased cNeT contained multiple polyclonal reactivities and key phenotypic features associated with high cell fitness and reduced cell exhaustion. VELOS Process 2 improves upon Process 1 by introducing additional culture media supplementation and an expansion-boosting stimulation cocktail during the co-culture period, without adding any time to the overall manufacturing process. Complementary GMP scale manufacturing data from Process 2 will be presented at the ESMO Immuno-Oncology Congress taking place December 8-11, 2021. This GMP scale manufacturing is identical to the process for Achilles' clinical studies and formed the basis of the Company's regulatory submissions to move the ongoing clinical studies to Process 2.
''We are thrilled to see that our Process 2 generated such a robust increase in cells while maintaining a highly functional phenotype and we look forward to treating patients with higher doses manufactured using VELOS Process 2,'' said Dr Sergio Quezada, Chief Scientific Officer of Achilles. ''Based on our experience with other cell therapies, we are confident that Process 2 will deliver doses able to elicit detectable clinical activity.''
Achilles' proprietary potency assay enabled the quantification of the proportion of tumour reactive cNeT within the expanded TIL population. Both processes generated CD4+ and CD8+ cells able to recognize clonal neoantigens. Process 2 delivered a polyclonal product with a median of five neoantigen reactivities (range 3 to 18) detected per patient. The immunophenotype of cNeT generated by Process 1 and 2 was largely similar, with the majority of the cells bearing an effector memory phenotype. Cells generated from both processes are also functionally similar as determined by their ability to secrete INF-?, IL-2 and TNF-a in response to polyclonal stimulus.
