Skip to content
DraconiticResearch
Search Sources API
189,105 studies31 sourcesUpdated 39 min ago
Peer-reviewedCC BY 4.0The Journal of Clinical Investigation

B cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma

  • Kavita M. Dhodapkar1,2
  • Antonio Matera1
  • Alyssa M. Duffy3
  • Azmain Taz1
  • Renee Julia Manalo3
  • Melinda Yushak3
  • Ragini Kudchadkar3
  • David H. Lawson3
  • Madhav V. Dhodapkar1
  1. 1Department of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
  2. 2Seattle Children’s Hospital, Seattle, Washington, USA.
  3. 3Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
Read full textPDFDOICite

Abstract

BACKGROUND: Combined checkpoint blockade (CCB) of programmed-death–1 (PD-1) and cytotoxic-T-lymphocyte–associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking.

METHODS: Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm A: ipi/nivo, n = 7) or with one cycle of rituximab (Arm B; ipi/nivo+rituximab, n = 7).

RESULTS: Patients receiving ipi/nivo+rituximab experienced lower rates of greater than grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE–free survival compared with those in ipi/nivo arm (2-year G3-irAE-free survival 86% versus 29%, P = 0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm B) prompted trial closure. Rituximab depleted pretherapy activated naive B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells.

CONCLUSION: B cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03719131.

FUNDING: NIH CA238471, AR077926, CA289978, and CA290302.

Related

  1. B cells and the therapeutic index of checkpoint blockade.
    Chuan-Yuan Li
    The Journal of clinical investigationPeer-reviewedCC BYFull textOncologyEurope PMCPMC
  2. Targeting RPL4 improves the therapeutic efficacy of PD-L1 blockade in liver fibrosis
    Jie Zhang, Chun-Ming Li, Lei Fang +7
    Cell Reports MedicinePeer-reviewedCC BY-NC 4.0Full textGeneral medicinePMC
  3. Immune checkpoint blockade activates macrophages and remodels the lymph node microenvironment in melanoma metastasis
    Ildefonso Silva-Junior, Fabio Carvalho de Souza, Tina Kwok +2
    Communications BiologyPeer-reviewedCC BY-NC-ND 4.0Full textOncologyCrossref
  4. Novel retinoic acid receptor-related orphan receptor gamma inverse agonist enhances checkpoint blockade in hepatocellular carcinoma: a preclinical mouse study
    S. Leo, I. Dhoparee-Doomah, S. Negi +6
    bioRxivPreprintAll rights reservedFull textOncologybioRxiv
  5. CCNE1 overexpression drives a cGAS-STING-dependent interferon response and sensitizes HRD-positive ovarian cancer to immune checkpoint blockade.
    Xueling Wang, Tian Chen, Zehua Wang +6
    Journal for immunotherapy of cancerPeer-reviewedCC BY-NCFull textObstetrics, gynaecology & paediatricsEurope PMC

Cite

BibTeXRIS
BibTeX
@article{dhodapkar2026cell,
  title = {{B cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma}},
  author = {Kavita M. Dhodapkar and Antonio Matera and Alyssa M. Duffy and Azmain Taz and Renee Julia Manalo and Melinda Yushak and Ragini Kudchadkar and David H. Lawson and Madhav V. Dhodapkar},
  journal = {The Journal of Clinical Investigation},
  year = {2026},
  month = aug,
  doi = {10.1172/jci205606},
  url = {https://doi.org/10.1172/jci205606},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - B cell depletion improves therapeutic index of combination checkpoint blockade in patients with advanced melanoma
AU  - Kavita M. Dhodapkar
AU  - Antonio Matera
AU  - Alyssa M. Duffy
AU  - Azmain Taz
AU  - Renee Julia Manalo
AU  - Melinda Yushak
AU  - Ragini Kudchadkar
AU  - David H. Lawson
AU  - Madhav V. Dhodapkar
PY  - 2026
DA  - 2026/08/25
JO  - The Journal of Clinical Investigation
DO  - 10.1172/jci205606
UR  - https://doi.org/10.1172/jci205606
AB  - BACKGROUND: Combined checkpoint blockade (CCB) of programmed-death–1 (PD-1) and cytotoxic-T-lymphocyte–associated protein-4 (CTLA-4) is highly active in melanoma but limited by significant morbidity from immune-related adverse events (irAEs). Effective strategies to prevent CCB-mediated irAEs are lacking.  METHODS: Patients with advanced melanoma were randomly assigned to receive standard of care ipilimumab and nivolumab alone (Arm A: ipi/nivo, n = 7) or with one cycle of rituximab (Arm B; ipi/nivo+rituximab, n = 7).  RESULTS: Patients receiving ipi/nivo+rituximab experienced lower rates of greater than grade-3(G3) irAEs (14% versus 57%) and superior G3-irAE–free survival compared with those in ipi/nivo arm (2-year G3-irAE-free survival 86% versus 29%, P = 0.01), without adverse impact on tumor regression or survival. G3 hypersensitivity reactions to rituximab (43% in Arm B) prompted trial closure. Rituximab depleted pretherapy activated naive B cells linked to autoimmunity and enhanced CCB-mediated induction of myeloid inflammation and CXCL13+ICOS+ CD4 T cells.  CONCLUSION: B cell depletion favorably modulates CCB-mediated immune activation and may reduce irAE risk.  TRIAL REGISTRATION: ClinicalTrials.gov NCT03719131.  FUNDING: NIH CA238471, AR077926, CA289978, and CA290302.
SN  - 0021-9738
SN  - 1558-8238
ER  -