Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Leukemia, Diseases, Lymphoma (any), Therapies, Biological Processes, Technology and Procedures, Clinically relevant, immune mechanism, NGS
We assessed 59 peripheral blood samples collected at screening (SCR, n=24), on Day 1 of Cycle 4 (C4, n=24) and Day 1 of Cycle 7 (C7, n=11). Patients were grouped based on best responses at C4 into responders (i.e. pts with partial response [PR, n=7] and very good PR [VGPR, n=8]), and non-responders (i.e. pts with minimal response [MR, n=2], stable disease [SD, n=5], or progressive disease [PD, n=2]). TRBV-TRBD-TRBJ gene rearrangements were subjected to paired-end NGS and raw reads (n=13,886,646 | median 239,969/sample) were processed through a purpose-built bioinformatics pipeline. Productive TRBV-TRBD-TRBJ rearrangements were taken into consideration (n=6,324,986 | median 100,738/sample) for the computation of clonotypes (i.e. TRB rearrangements with identical TRBV gene usage and amino acid complementarity-determining region 3 sequence). Overall, 325,789 distinct clonotypes (median 4,535 clonotypes/sample) were analyzed. The TR repertoire displayed clonal T cell expansions in both groups (responders/non-responders) in all pre/post-treatment timepoints. Clonality increased after treatment for both responders and non-responders in all assessed timepoints, with statistical significance at C4 in both groups (median cumulative frequency of the 10 most expanded T cell clonotypes/sample in responders: 31.6% pre-treatment vs 43% C4 post-treatment, p=0.009; and, in non-responders: 19.8% pre-treatment vs 39.6% C4 post-treatment, p=0.009). In both groups, the clonotype repertoire appeared to be renewed. Interestingly, in the responders' group a significant shift was noticed in the major clonotype repertoire at screening vs C4. In particular, the 10 most expanded clonotypes/sample at C4 represented expansions of clonotypes present at very low frequency at screening, whereas the most expanded clonotypes at screening decreased or even diminished post-treatment. Additionally, although the major post-treatment clonotype at C4 also dominated at C7 in most cases, certain lower frequency clonotypes at C4 emerged among the top-10 at C7. Thirteen shared clonotypes were identified amongst the post-treatment repertoires of different patients but not in other entities in public databases, raising the possibility that they may be "MM-specific" and selected by common MM-associated antigens. Finally, flow cytometry analysis revealed a significant increase post treatment in the percentage of CD3+ T cells (median frequency at SCR 63% vs 78.7% at C4 | p=0.0045 and 87.4% at C7 | p=0.0009), driven mostly by the expansion of the CD8+ T cell compartment (median frequency at SCR 31.4% vs 45.3% at C4 | p=0.0045 and 53.8% at C7 | p=0.001) in both groups.
In conclusion, we document T cell clonal expansions and clonal drift after daratumumab treatment in MM. Our results suggest that daratumumab acts through renewing the greatest part of the pre-treatment TR clonotype repertoire, suggesting dynamic changes of the T cell compartment under treatment, a claim also supported by the significant increase in CD8+ cytotoxic T cell numbers overtime. The significant post-treatment expansion of certain low-frequency pre-treatment clones in responders raises the intriguing hypothesis that daratumumab treatment may have led to the outgrowth of anti-MM T cell clones, arguably contributing to clinical response.
Disclosures: Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Hatjiharissi: Abbvie: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Katodritou: Theagenion Cancer Hospital: Current Employment; Takeda: Honoraria, Other: Expenses, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gavriatopoulou: Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Delimpasi: GENESIS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Symeonidis: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding. Stamatopoulos: AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Dimopoulos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Terpos: Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria. Chatzidimitriou: Janssen: Research Funding.
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