Discussion
ovarian cancer, tumor, cancers, Tumor, cancer, non-sarcoma cancers, MRCLS, CRS, early-onset, tumors
OVARIAN CANCER, TUMOR, CANCERS, TUMOR, CANCER, PATHOPHYSIOLOGY, PROLIFERATIVE, TUMORS
In this phase 1 trial, we evaluated the safety, clinical activity and translational effects of afami-cel in HLA-A*02Afami-cel-related CRS occurred in 55% of all patients and was typically low-grade, early-onset, post-infusion and reversible in all cases with the administration of anti-IL-6(R) monoclonal antibody treatment when indicated. Consistent with the known monocyte–macrophage-centric pathophysiology of CRS, elevations in serum cytokines (including IFNγ, IL-6 and GMCSF) were associated with increasing CRS grades. The overall incidence and severity of ICANS/encephalopathy was low, with no reported cases in patients with SS. Although additional neurological AEs were reported across tumor types, there was no consistent pattern to suggest a definite causal relationship with afami-cel. The safety findings reported here are consistent with those observed in patients with cancer undergoing LD chemotherapy and cellular therapy, including treatment with chimeric antigen receptor T cells or NY-ESO-1 T cellsPatients treated in the trial had nine different cancers with heterogenous MAGE-A4 expression, and most patients with therapeutic responses had high H-scores. The ORR of 24% in the overall population was primarily due to clinical activity observed in SS. Responses were limited in non-sarcoma cancers, perhaps due to small numbers of patients with specific cancer types or lower MAGE-A4 expression relative to SS. Although the number of patients with SS was small, the emergent ORR of 44%, median PFS of 20.4 weeks and median OS of 58.1 weeks are better than the historical low ORRs reported for current standard-of-care therapies, including pazopanib and trabectedin, used in the post-first-line metastatic settingPreliminary evaluation of pharmacokinetic and pharmacodynamic relationships associated with afami-cel dose escalation used peak cell persistence and peak serum IFNγ levels as prototypical pharmacokineticand pharmacodynamic markers, respectively. When considering the subset of patients with ovarian cancer across all dosing groups, increases in afami-cel doses were associated with progressively increasing peak cell persistence and peak IFNγ levels (Supplementary Table The serum cytokine response profile indicated an IFNγ-driven mechanism of action as well as emerging biomarkers of anti-tumor response. Tumor analyses supported the co-localization of afami-cel with cancer cells and resident immune cells in tumors, with evidence of activated and proliferative intra-tumoral T cell states and adaptive immune responses. Because the ongoing phase 2 SPEARHEAD-1 trial will have dosed ~100 patients with SS and MRCLS with afami-cel at completion, confirmation of these preliminary translational analyses may be possible in future pooled analyses. This will include a deeper evaluation of the potentially complex inter-relationship between immunological components of the tumor microenvironment and dynamic temporal changes in afami-cel phenotype and function after infusion.In summary, our findings demonstrate that afami-cel was well tolerated and suggest that it could be a promising therapy for patients with metastatic SS who have received prior ifosfamide treatment. Limitations to the interpretation of the response rate in SS include the small sample size and confounding effect of LD. Nevertheless, the encouraging results warrant further study, and additional data in metastatic SS will be evaluated in the phase 2 SPEARHEAD-1 trial