Abstract

Background. Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including copy gains of 9p24.1/ CD274(PD-L1) / PDCD1LG2 (PD-L2) and perturbed MHC class I and class II expression and associated antigen presentation. The identification of 9p24.1 alterations and PD-1 ligand overexpression in cHL prompted clinical evaluation of PD-1 blockade in this disease. In pilot and registration studies, response rates of ~70% were seen in patients (pts) with relapsed/refractory (R/R) cHL. However, the described deficits in HRS cell expression of MHC class I and II prompt speculation regarding the mechanism of action of PD-1 blockade in R/R cHL.

We have assessed 9p24.1 alterations and PD-L1, beta 2 microglobulin (β2M), MHC class I and MHC class II expression in HRS cells from pts with R/R cHL who received nivolumab (nivo) in Cohorts B and C of CheckMate 205. All pts were previously treated with myeloablative autologous stem cell transplantation (ASCT) and brentuximab vedotin for multiply relapsed disease before study entry.

Methods. Using archival tumor biopsies and published methods (JCO 2016; 34:2690 and CIR 2016; 4:910), 9p24.1 alterations were evaluated via fluorescence in situ hybridization with probes encompassing PD-L1, PD-L2 and a centromeric control; PD-L1, β2M, MHC class I and MHC class II expression were separately assessed in dual immunohistochemical assays that included PAX5 to identify HRS cells. Responses to nivo - complete remission (CR), partial remission, stable disease, or progressive disease - and progression-free survival (PFS) were determined by an independent radiological review committee. To account for differences in immune cell reconstitution following ASCT, pts treated with nivo £12 mo and >12 mo after ASCT were also analyzed separately.

Results and Conclusions. Ninety-seven pts had tumor biopsies that were evaluable for 9p24.1 alterations and PD-L1 expression. We detected 9p24.1 alterations in all evaluable cHL biopsy specimens and found a significant association between the magnitude of 9p24.1 copy gain and PD-L1 expression on HRS cells (p=0.001). Pts who did not respond to nivo (and had progressive disease) had significantly lower magnitude 9p24.1 alterations and PD-L1 expression on HRS cells (p=0.006 and p=0.018, respectively). In contrast, higher magnitude 9p24.1 alterations and PD-L1 expression were associated with longer PFS following nivo therapy (p<0.001 and p=0.026, respectively). Higher magnitude 9p24.1 alterations were similarly predictive for prolonged PFS in pts with £12 mo or >12 mo between ASCT and nivo therapy. Higher level PD-L1 protein expression was also significantly associated with prolonged PFS in pts with >12 mo between ASCT and nivo therapy (p=0.027), but not in those with a £12-mo interval. In the latter group of pts, who were still reconstituting their immune repertoire and tumor microenvironment following ASCT, PD-L1 expression may be driven by a combination of genetic alterations and additional microenvironmental signals that would not be reflected in the archival tumor biopsy specimens evaluated for PD-L1 expression.

Seventy-two pts had tumor biopsies that were evaluable for β2M, MHC class I and MHC class II expression. Strikingly, 92% (11/12) of pts who achieved a CR on nivo had tumors that were negative for β2M/MHC class I. Moreover, PFS was unrelated to HRS cell expression of β2M or MHC class I. Similar results were obtained in pts with intervals of £12 mo and >12 mo between ASCT and nivo therapy.

In contrast, 92% (11/12) of pts with CRs to nivo had tumors with membranous MHC class II expression on HRS cells. MHC class II expression on HRS cells was not predictive for PFS in pts who were treated with nivo £12 mo following ASCT, likely reflecting differences in the tumor microenvironment at biopsy and subsequent study entry. However, in pts who received nivo >12 mo after ASCT, MHC class II expression on HRS cells was highly predictive for prolonged PFS (p=0.014).

Our data indicate that in cHL, clinical responses to PD-1 blockade do not require MHC class I-mediated antigen presentation by HRS cells. In contrast, MHC class II expression on HRS cells is predictive for clinical response to PD-1 blockade.

Disclosures

Younes: Takeda Millenium: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer: Honoraria; Incyte: Honoraria; Novartis: Research Funding; Johnson & Johnson: Research Funding; Curis: Research Funding; Merck: Honoraria; Seattle Genetics: Honoraria; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Sanofi: Honoraria; Celgene: Honoraria. Fanale: ADC THERAPEUTICS: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; ADC THERAPEUTICS: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; GENENTECH: Research Funding; ONYX: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; MOLECULAR TEMPLATES: Research Funding; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; ONYX: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zinzani: Pfizer: Other: Advisory board; Karyopharma: Other: Advisory board; Janssen: Other: Advisory board; Gilead: Other: Advisory board; Celgene: Other: Advisory board; Roche: Other: Advisory board; Takeda: Other: Advisory Board; Sandoz: Other: Advisory board. Timmerman: Genmab: Consultancy, Equity Ownership; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Research Funding; ImmuneGene: Research Funding. Collins: Celleron: Consultancy; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Ramchandren: Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Cohen: LAM Therapeutics, Inc: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Takada: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. De Boer: Eisai: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Other: Non-restricted grant for research in head and neck cancer; Astellas: Other: member of Independent Data Monitoring Committee; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Kuruvilla: Celgene: Honoraria, Research Funding; Roche: Research Funding; Karyopharm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Merck: Honoraria. Savage: Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Trneny: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell: Affimed: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding. Sacchi: Bristol-Myers Squibb: Employment. Farsaci: Bristol-Myers Squibb: Employment, Equity Ownership, Patents & Royalties. Sumbul: Bristol-Myers Squibb: Employment. Armand: Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Affimed: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding; Infinity: Consultancy; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding; Genmab: Consultancy; Roche: Research Funding. Neuberg: Synta Pharmaceuticals: Other: Stock shares. Rodig: Bristol-Myers Squibb: Honoraria, Research Funding. Shipp: Bayer: Research Funding; Takeda: Other: Scientific Advisory Board; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Other: Scientific Advisory Board; Merck: Other: Scientific Advisory Board; Cell Signaling: Honoraria; AstraZeneca: Honoraria.

Author notes

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Asterisk with author names denotes non-ASH members.