Combined IL-21-primed polyclonal CTL plus CTLA4 blockade controls refractory metastatic melanoma in a patient

Abstract

Adoptive transfer of peripheral blood-derived, melanoma-reactive CD8(+) cytotoxic T lymphocytes (CTLs) alone is generally insufficient to eliminate bulky tumors. Similarly, monotherapy with anti-CTLA4 infrequently yields sustained remissions in patients with metastatic melanoma. We postulated that a bolus of enhanced IL-21-primed polyclonal antigen-specific CTL combined with CTLA4 blockade might boost antitumor efficacy. In this first-in-human case study, the combination successfully led to a durable complete remission (CR) in a patient whose disease was refractory to both monoclonal CTL and anti-CTLA4. Long-term persistence and sustained anti-tumor activity of transferred CTL, as well as responses to nontargeted antigens, confirmed mutually beneficial effects of the combined treatment. In this first-in-human study, Chapuis et al. demonstrate that the combination of adoptive cellular therapy with CTLA4 blockade induces long-term remission in a melanoma patient resistant to both modalities administered serially and individually.

Figure 1.

Tumor regressions after melanoma-reactive polyclonal CTL combined with anti-CTLA4. (A) Timeline of successive therapies. (B) Kinetics of response for three target lesions (y axis) spanning 5 yr (x axis). (C) Serial PET (leftmost image) and CT images at indicated time points. Arrows indicate the location of the right hilar (blue) and subcarinal (red) masses. (D) Photograph of the patient's depigmented eyelashes and eyebrows ∼5 mo after the start of the combined treatment.

Figure 2.

Kinetics, clonality, phenotype, and function of monoclonal and polyclonal CTL in vivo. (A) Percent multimer⁺CD8⁺ T cells (left y axis) in PBMCs (solid circles) collected before and at defined time points after monoclonal (dashed line) and polyclonal (solid line) CTL infusions (indicated). Gray shaded areas indicate anti-CTLA4 treatment. (B and C) Inset pie charts represent individual clonotypes composing the monoclonal (B) and polyclonal (C) infused CTL. Graphs track the corresponding unique (B) and sum of clonotypes (C) as a percentage of total CD8⁺ T cells (y axis). Time points in which the corresponding clones were assessed but not detected (nd) are indicated. *, only clone TCR-13 was detected immediately before the polyclonal infusion with a frequency of 0.054%. (D) Percent expression of CD28, CD62L, CCR7 (long-lived memory markers, blue shade), PD1 (activation/exhaustion marker, red shade), IFN-γ, TNF, and IL-2 (functional markers, green shade) on polyclonal (top) and monoclonal (bottom) infused CTL. (E and F) The same analysis performed on multimer⁺ cells 1 d (E) and 86 d (F) in vivo after infusion.

Figure 3.

Reactivity to nontargeted epitopes. Heat map summarizing responses of CD8⁺ and CD4⁺ T cells independent of HLA restriction to pools of 20–30 peptides spanning MART1 (red), NY-ESO1 (blue), gp100 (green), tyrosinase (violet), and MAGE-A3 (orange). The color scale (light to dark) reflects the response magnitude at indicated time points before and after administration of monoclonal and polyclonal CTL during the patients’ treatment course (top schema). Inset numbers indicate IFN-γ spots per 10⁵ PBMC for each peptide pool.