Immune regulatory antibodies: Are they the next advance? Journal Article
| Authors: | Wolchok, J. D.; Yang, A. S. ; Weber, J. S. |
| Article Title: | Immune regulatory antibodies: Are they the next advance? |
| Abstract: | During the past decade, new insights into the mechanisms by which T-cell activation and proliferation are regulated have led to the identification of checkpoint proteins that either up-or down-modulate T-cell reactivity. In the presence of active malignancy, pathophysiologic inhibition of T-cell activity may predominate over stimulation. A number of antibodies have been generated that can block inhibitory checkpoint proteins or promote the activity of activating molecules. In murine models, their use alone or with a vaccine strategy has resulted in regression of poorly immunogenic tumors and cures of established tumors. The prototypical immune regulatory antibodies are those directed against cytotoxic T-lymphocyte antigen-4, a molecule present on activated T cells. In this review, the preclinical rationale and clinical experience with 2 anticytotoxic T-lymphocyte antigen-4 antibodies are extensively discussed, demonstrating that abrogation of an immune inhibitory molecule can result in significant regression of tumors and longlasting responses. The unique kinetics of antitumor response and the characteristic immune-related side effects of ipilimumab are also discussed. This clinical efficacy of this promising antitumor agent has been evaluated in 2 randomized phase III trials, whose results are eagerly awaited. Programmed death (PD)-1 is another immune inhibitory molecule against which an abrogating human antibody has been prepared. Initial preclinical testing with anti-PD-1 and anti-PD-L1 has shown encouraging results. Stimulatory molecules such as CD40, 41-BB, and OX-40 are also targets for antibody binding and activation, not blockade, and early dose ranging trials with antibodies against all 3 have shown that they can mediate regression of tumors, albeit with their own spectrum of side effects that are different from those that occur with abrogation of immune inhibition. Copyright © Lippincott Williams & Wilkins. |
| Keywords: | cancer chemotherapy; cancer survival; treatment response; leukemia; cancer surgery; survival rate; unclassified drug; acute granulocytic leukemia; overall survival; drug tolerability; fatigue; review; hepatitis; advanced cancer; area under the curve; diarrhea; drug efficacy; drug safety; nonhuman; side effect; drug targeting; paclitaxel; cancer radiotherapy; temozolomide; antineoplastic agent; protein function; cd8+ t lymphocyte; animals; carboplatin; cytotoxic t lymphocyte antigen 4 antibody; dacarbazine; interleukin 2; ipilimumab; ticilimumab; melanoma; metastasis; ovary cancer; breast cancer; anemia; thrombocytopenia; antineoplastic activity; kidney carcinoma; immunoregulation; arthralgia; chill; drug dose escalation; fever; prostate cancer; pruritus; rash; lymphocyte activation; immune tolerance; antibodies, monoclonal; nonhodgkin lymphoma; rigor; fibrosarcoma; colon cancer; arthritis; breast tumor; pancreatitis; cancer immunization; cd4+ t lymphocyte; t-lymphocytes, cytotoxic; lymphoma; ovary carcinoma; single drug dose; adoptive transfer; colitis; pleura effusion; tumor necrosis factor receptor; prostate adenocarcinoma; maximum plasma concentration; large cell lymphoma; liver function test; antigens, cd; drug half life; peptide vaccine; colon carcinoma; cytotoxic t lymphocyte antigen 4; granulocyte macrophage colony stimulating factor vaccine; antibody; immunoglobulin g1 antibody; endocrine disease; t lymphocyte activation; drug induced disease; myeloma; checkpoint; ct 011; programmed death 1 ligand 1; programmed death 1 receptor; stimulation; t cell; dose time effect relation; budesonide; hypophysitis; thyrotropin blood level; vitiligo; conjunctivitis; cd40 antigen; corticosteroid therapy; immune; call antibody; cd137 antigen; cd40 antibody; cp 870893; mdx 1105; mdx 1106; programmed death 1 ligand 1 antibody; programmed death 1 receptor antibody; receptor antibody; sgn 40; tumor necrosis factor receptor ox 40 antibody; cytokine release syndrome |
| Journal Title: | The Cancer Journal |
| Volume: | 16 |
| Issue: | 4 |
| ISSN: | 1528-9117 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2010-07-01 |
| Start Page: | 311 |
| End Page: | 317 |
| Language: | English |
| DOI: | 10.1097/PPO.0b013e3181eb3381 |
| PUBMED: | 20693841 |
| PROVIDER: | scopus |
| PMCID: | PMC4052949 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CAJOC" - "Source: Scopus" |
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