Dataset Information

Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy.

ABSTRACT:

Objectives

A diverse intratumoral T-cell receptor (TCR) repertoire is associated with improved survival in diffuse large B-cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R-CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes.

Methods

We sequenced the third complementarity-determining region of TCRβ in tumor samples, blood at pre-therapy and after four cycles of R-CHOP in 35 patients enrolled in ALLGNHL21 trial in high-risk DLBCL. We correlated the TCR diversity metrics with iPET status, gene expression profiles and HLA-class I genotypes. We then sequenced the FACS-sorted peripheral blood T cells in six patients, and pentamer-sorted EBV-specific CD8⁺ T cells in one patient from this cohort.

Results

Compared with iPET^- patients, the intratumoral TCR repertoire in iPET⁺ patients was characterised by higher cumulative frequency of abundant clonotypes and higher productive clonality. There was a variable overlap between circulating and intratumoral repertoires, with the dominant intratumoral clonotypes more likely to be detected in the blood. The majority of shared clonotypes were CD8⁺ PD-1^HI T cells, and CD8⁺ T cells had the largest clonal expansions in tumor and blood. In a patient with EBV⁺ DLBCL, EBV-specific intratumoral clonotypes were trackable in the blood.

Conclusion

This study demonstrates that clonally expanded intratumoral TCR repertoires are associated with iPET⁺ and that the blood can be used to track tumor-associated antigen-specific clonotypes. These findings assist the rationale design and therapeutic monitoring of immunotherapeutic strategies in DLBCL.

SUBMITTER: Shanavas M

PROVIDER: S-EPMC8548874 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy.

Shanavas Mohamed M Law Soi-Cheng SC Hertzberg Mark M Hicks Rodney J RJ Seymour John F JF Li Zhixiu Z Merida de Long Lilia L Nath Karthik K Sabdia Muhammed B MB Gunawardana Jay J Gandhi Maher K MK Keane Colm C

Clinical & translational immunology 20211027 11

<h4>Objectives</h4>A diverse intratumoral T-cell receptor (TCR) repertoire is associated with improved survival in diffuse large B-cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R-CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes.<h4>Methods</h4>We seq ...[more]

PMID: 34745610

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Project description:Background: Over 13,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton's tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability. Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints. Discussion: ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL. Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN 13626902 (registered 07 March 2017).

Dataset Information

Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy.

Objectives

Methods

Results

Conclusion

Publications

Intratumoral T-cell receptor repertoire is predictive of interim PET scan results in patients with diffuse large B-cell lymphoma treated with rituximab/cyclophosphamide/doxorubicin/prednisolone/vincristine (R-CHOP) chemoimmunotherapy.

Similar Datasets

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