Biologic and immunomodulatory events after CTLA‐4 blockade with ticilimumab in patients with advanced malignant melanoma

  title={Biologic and immunomodulatory events after CTLA‐4 blockade with ticilimumab in patients with advanced malignant melanoma},
  author={James M. Reuben and Bang‐Ning Lee and Changping Li and Jesús Gómez-Navarro and Viviana A Bozon and Charla A. Parker and Ingrid M. Hernandez and Carolina Gutierrez and Gabriel Lopez-Berestein and Luis H Camacho},
T‐regulatory (TR) cells expressing cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) maintain peripheral immune tolerance and negatively affect host immune responses against cancer. The immunobiologic effects of ticilimumab, a human monoclonal antibody against CTLA‐4, was administered to patients with metastatic melanoma who participated in a Phase I/II clinical trial. 

Current Experience With CTLA4-blocking Monoclonal Antibodies for the Treatment of Solid Tumors

The key limitations for broader applicability of this mode of therapy are better definition of the mechanism that leads to tumor rejection and the validation of favorable observations in single-arm studies into prospectively randomized clinical trials.

Overcoming immunological tolerance to melanoma: Targeting CTLA‐4

  • F. Hodi
  • Biology, Medicine
    Asia-Pacific journal of clinical oncology
  • 2010
A clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte‐macrophage colony stimulating factor with periodic infusions of CTLA‐4 blocking antibodies resulted in clinically significant anti‐tumor immunity without grade 3 or 4 toxicity in most patients.

Update on anti-CTLA-4 antibodies in clinical trials

Preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events are reviewed.

CTLA‐4 to overcome immunological tolerance to melanoma

In recent trials, patients who were vaccinated with autologous tumor cells engineered to secrete granulocyte–macrophage colony‐stimulating factor, and were then infused with anti‐CTLA‐4 antibodies, demonstrated clinically‐significant antitumor immunity without grade‐3 or ‐4 toxicity in most patients.

Anti-GBM disease following CTLA4 blockade in a patient with metastatic melanoma

A case of a 50-year-old man presenting with cough, fever, macroscopic haematuria and oligoanuric kidney failure following treatment with the CTLA4 antagonist tremelimumab for metastatic malignant melanoma is reported.

Anti-CTLA-4 therapy in melanoma: Role of ipilimumab (MDX-010)

Treatment with the anti-CTLA-4 monoclonal antibody ipilimumab (MDX-010) seems to prevent this anergy and permits specific T-lymphocyte activation against tumor antigens.

Modulation of CTLA-4 and GITR for cancer immunotherapy.

The experience with anti-CTLA-4 therapy and the durable clinical benefit observed provide proof of principle to effective antitumor immune modulation and the promise of future clinical immune modulatory antibodies.

Clinical development of the anti-CTLA-4 antibody tremelimumab.

  • A. Ribas
  • Biology, Medicine
    Seminars in oncology
  • 2010
The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.

CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?

Tremelimumab seems to be a valuable strategy to revive reactive memory T cells anergized in the context of stage IV melanoma, and this work suggests that memory T-cell resistance to Treg resulting from anti–CTLA-4 treatment might be a biological activity marker for tremelimumAB in patients with melanoma.

Targeting T Cell Co-receptors for Cancer Therapy.




Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

  • G. PhanJ. Yang S. Rosenberg
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
This study establishes CTLA-4 as an important molecule regulating tolerance to “self” antigens in humans and suggests a role for CTla-4 blockade in breaking tolerance to human cancer antIGens for cancer immunotherapy.

CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy.

Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response.

Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma.

Dose-related autoimmune adverse events, predominantly skin and GI toxicities, were reversible and patients mounted an antigen-specific immune response to a peptide vaccine when combined with a human anti-CTLA-4 antibody.

Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.

CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.

Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer.

  • E. KwonA. Hurwitz J. Allison
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1997
A novel syngeneic murine prostate cancer model is established and in vivo antibody-mediated blockade of CTLA-4 enhances antiprostate cancer immune responses, suggesting that appropriate manipulation of T cell costimulatory and inhibitory signals may provide a fundamental and highly adaptable basis for prostate cancer immunotherapy.

Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

It is reported here that the ligand of PD-1 (PD-L1), an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells, is a member of the B7 gene family.

Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion

The authors declare competing financial interests: see the website ( for details.

CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells

It is demonstrated that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti- CD3 and anti-CD28.

Regulation of murine chronic colitis by CD4+CD25– programmed death‐1+ T cells

Results indicate that the CD4+CD25–PD‐1+ T’cells contain substantial amounts of TR cells that are involved in the maintenance of peripheral tolerance.