|Pronunciation||i pi lim′ ue mab|
|Synonyms||BMS-734016, MDX-010, MDX-101|
|AHFS/Drugs.com||Consumer Drug Information|
|Chemical and physical data|
|Molar mass||148634.914 g/mol|
|(what is this?)|
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to function.
Ipilimumab was approved by the U.S. FDA in 2011 for the treatment of melanoma, a type of skin cancer. It is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer and metastatic hormone-refractory prostate cancer.
The concept of using anti-CTLA4 antibodies to treat cancer was first developed by James P. Allison while he was director of the Cancer Research Laboratory at the University of California, Berkeley. Clinical development of anti-CTLA4 was initiated by Medarex, which was later acquired by Bristol-Myers Squibb. As of 2013 the cost was $120,000 for a course of treatment. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015. Allison later was the co-winner of the 2018 Nobel Prize in Physiology or Medicine.
- 1 Approvals and indications
- 2 Adverse effects
- 3 Interactions
- 4 Mechanism of action
- 5 Identifying patients most likely to respond
- 6 Clinical trial history
- 7 Combination trials
- 8 Development
- 9 References
- 10 External links
Approvals and indications
Ipilimumab was approved by US FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. It was later approved by the US FDA on October 28, 2015 for stage 3 patients as adjuvant therapy. On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease." Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma in November 2012.
Ipilimumab treatment has been associated with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation; these occur in 10-20% of people and are a major drawback of this drug. Most of the serious adverse effects are associated with the gastro-intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also fever, breathing or urinating problems. A "risk evaluation and mitigation strategy" informs prescribers of the potential risks.
This section needs expansion. You can help by adding to it. (March 2016)
Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.
Systemic corticosteroids should be avoided before starting ipilimumab; however, systemic corticosteroids may be used to treat an immune-related adverse reaction that arises from ipilimumab treatment.
Mechanism of action
T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.
Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.
Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells. In 2014 a study indicated that the antibody works by allowing the patients' T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen.
Identifying patients most likely to respond
During “cancer immunoediting", tumor cells can produce antigens that provoke a reduced immune response and/or establish an immunosuppressive tumor microenvironment (TME). The latter can arise as a consequence of repeated, ineffective T cell stimulation. This triggers the checkpoint that ipilumumab targets. Many patients do not benefit from treatment, which may be related to reduced mutation load and/or missense point mutation-derived neoantigens. Tumor antigens can either be improperly expressed normal proteins or abnormal proteins with tumor-specific expression. Somatic cancer mutations can produce “nonself” tumor-specific mutant antigens (neoantigens).
Sequencing and epitope prediction algorithms identified neoantigens in mouse tumors that functioned as tumor-specific T cell targets. Neoantigens were recognized by T cells in melanoma patients and were likely the major contributor to positive clinical effects of adoptive cell transfer. Mouse models established that neoantigens were the targets of T cells activated by checkpoint blockade therapy and that synthetic long peptides comprising these neoantigens were effective when administered as vaccines with CTLA-4 and/or PD-1 mAbs. Cancers with higher mutation burdens, and an associated likelihood of expressing neoantigens, appear most likely to respond to checkpoint therapy. In melanoma and certain other cancers, the numbers of mutations and neoantigens correlate with patient response. Increased PD ligand 2 (PD-L2) transcript expression and an immune “cytolytic” gene signature also correlated with neoantigen load and tumor response. CTLA-4 expression was a response indicator, which along with PD-L2 were likely expressed in tumor-infiltrating immune cells. An inflamed TME prior to treatment is also associated with response.
Nearly all neoantigens in one study were patient-specific and most likely reflected mutations that do not directly contribute to tumorigenesis. However, none revealed features or motifs exclusive to responders.
Clinical trial history
In the 2000s, ipilimumab clinical trials were under way on patients with melanoma, renal cell carcinoma, prostate cancers, urothelial carcinoma and ovarian cancer. By 2007, there were two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma. The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea, and hepatitis.
In 2010, a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6 months for those treated with gp100, an experimental vaccine (n=676). The one year survival rate was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those receiving both. The Phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). The study tested ipilimumab alone, ipilimumab with gp100, and the vaccine alone. Patients had a higher survival rate with ipilimumab alone, however it is not fully clear whether the vaccine caused toxicity, which would make the drug perform better by comparison. Ipilimumab gained FDA approval in early 2011.
In 2008/09 Medarex performed a phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). Some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.
On June 19, 2009, the Mayo Clinic reported two prostate cancer patients involved in a phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result. This press report however was criticized as premature and somewhat inaccurate. The clinical trials were still at an early stage and were run alongside other treatments – which could have been the real explanation for the tumor shrinkage. It was too early to say whether ipilimumab made any difference.
In 2016, a phase II study using ipilimumab and nivolumab in AR-V7-expressing metastatic castration-resistant prostate cancer was opened. AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.
Medarex ran a phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cell and non-small cell lung cancer. It was scheduled to run from February 2008 to December 2011.
This section needs to be updated.(March 2016)
To increase response rate and reduce adverse reactions, various drug combinations are being tested.
In 2013 a trial was running that compared ipilimumab alone against ipilimumab in combination with nivolumab. The response rate (tumours shrinking by at least 30%) was 58% for the combination, 44% for nivolumab alone, and 19% for ipilimumab alone. This combination gained FDA approval for melanoma in Oct 2015.
In March 2014, an open-label, randomized, two agent, single center trial started combining ipilimumab with phosphatidylserine-targeting immunotherapy bavituximab for the treatment of advanced melanoma. The number of treated patients in arm A (ipilimumab plus bavituximab) was to be 16, with 8 in arm B (ipilimumab only). The trial was expected to complete in March 2016. Previous, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
This section needs to be updated.(May 2014)
Following the 1987 cloning of CTLA-4 in mice, its conservation in humans and similarities with CD28 were soon noticed. CD28 at that time was a recently identified "T cell costimulatory" molecule important for T cell activation. Anti-CTLA-4 blockade, the invention that gave rise to ipilimumab, was conceived by Allison and Krummel along with CTLA-4's inhibitory role in T cell activation. They were able to demonstrate that CTLA-4 signaling in T cells inhibited T cell responses. They then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens. Leach, a new postdoctoral fellow, was tasked by Allison with applying these in tumor models. Antibody-treated mice showed significantly less cancer growth than the controls.
Bluestone and Linsley separately studied the similarities between CD28 and CTLA-4. Bluestone’s lab published studies, one together with Krummel and Allison, for in vitro studies of CTLA-4 function. In collaboration with Mark Jenkins, they were able to see effects of anti-CTLA-4 antibodies in vivo in an immunization setting, but did not effectively carry this into tumor biology. Linsley and colleagues had made antibodies against CTLA-4 three years prior to those of Krummel/Allison or Walunas/Bluestone. They concluded that the molecule functioned similarly to CD28 and was a "positive costimulator". They apparently did not pursue CTLA-4 tumor targeting, although BMS licensed the Allison/Leach/Krummel patent through their acquisition of Medarex and the fully humanized antibody MDX010, which later became ipilimumab.
- "Yervoy, ipilimumab (BMS-734016) - Product Profile - BioCentury". BioCentury Online Intelligence. BioCentury Publications. Retrieved 11 August 2016.
- USAN. "STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL - ipilimumab" (Press release). American Medical Association (AMA). Retrieved 2013-01-12.
- Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
- Antoni Ribas (28 June 2012). "Tumor immunotherapy directed at PD-1". New England Journal of Medicine. 366 (26): 2517–9. doi:10.1056/nejme1205943. PMID 22658126.
- Lacroix, Marc (2014). Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. ISBN 978-1-63321-687-7.
- Pollack, Andrew (May 29, 2015). "New Class of Drugs Shows More Promise in Treating Cancer". New York Times. Retrieved May 30, 2015.
- Clinical trial number NCT00527735 at ClinicalTrials.gov Phase II Study for Previously Untreated Subjects With Non Small Cell Lung Cancer (NSCLC) or Small Cell Lung Cancer (SCLC)
- First-Line Gemcitabine, Cisplatin + Ipilimumab for Metastatic Urothelial CarcinomaClinical trial number NCT01524991 at ClinicalTrials.gov
- Clinical trial number NCT00323882 at ClinicalTrials.gov Phase I/II Study of MDX-010 in Patients With Metastatic Hormone-Refractory Prostate Cancer (MDX010-21) (COMPLETED)
- Leach DR, Krummel MF, Allison JP (1996). "Enhancement of antitumor immunity by CTLA-4 blockade". Science. 271 (5256): 1734–6. doi:10.1126/science.271.5256.1734. PMID 8596936.
- "The Story of Yervoy (Ipilimumab)".
- Couzin-Frankel, Jennifer (20 December 2013). "Breakthrough of the Year: Cancer Immunotherapy". Science. 342 (6165): 1432–3. doi:10.1126/science.342.6165.1432. PMID 24357284.
- Lasker Foundation. "Deep brain stimulation for Parkinson's disease". The Lasker Foundation.
- "The Nobel Prize in Physiology or Medicine 2018 to James P. Allison and Tasuku Honjo".
- Jefferson E (2011-03-25). "FDA approves new treatment for a type of late-stage skin cancer" (Press release). U.S. Food and Drug Administration (FDA). Retrieved 2011-03-25.
- Pollack, Andrew (2011-03-25). "Approval for Drug That Treats Melanoma". The New York Times. Retrieved 2011-03-27.
- Drugs.com: Yervoy
- "FDA approves Yervoy to reduce the risk of melanoma returning after surgery".
- Notice of Decision for YERVOY[dead link]
- "Bristol-Myers Squibb Receives Positive Decision from National Institute of Health and Clinical Excellence (NICE) for YERVOY® (ipilimumab)" (Press release). November 1, 2012. Retrieved December 17, 2012.
- Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F (2015). "Metastatic melanoma - a review of current and future treatment options". Acta Derm Venereol. 95 (5): 516–524. doi:10.2340/00015555-2035. PMID 25520039.
- Johnson DB, Peng C, Sosman JA (2015). "Nivolumab in melanoma: latest evidence and clinical potential". Ther Adv Med Oncol. 7 (2): 97–106. doi:10.1177/1758834014567469. PMC 4346215. PMID 25755682.
- "FDA Rubber-Stamps Bristol-Myers Squibb's Melanoma mAb". Genetic Engineering & Biotechnology News. 2011-03-28. Retrieved 2011-03-28.
- "Two Cases of Myasthenia Gravis Seen With Ipilimumab". 2014-04-29.
- "Arava (leflunomide) [package insert]" (PDF). Australia: Sanofi-Aventis, July 2014. Retrieved 2 November 2014.
- Ribas, Antoni; Hodi, F. Stephen; Callahan, Margaret; Konto, Cyril; Wolchok, Jedd (April 4, 2013). "Hepatotoxicity with combination of vemurafenib and ipilimumab". N Engl J Med. 368 (14): 1365–6. doi:10.1056/NEJMc1302338. PMID 23550685.
- "Zelboraf (vemurafenib) [package insert]" (PDF). South San Francisco, CA: Genentech USA, Inc.; March 2013. Retrieved 29 October 2014.
- "Yervoy (ipilimumab) [package insert]" (PDF). Princeton, NJ: Bristol-Myers Squibb Company; Dec 2013. Archived from the original (PDF) on 6 February 2015. Retrieved 29 October 2014.
- "Yervoy Annex I: Summary of Product Characteristics" (PDF). Retrieved 2 November 2014.
- Tarhini AA, Iqbal F (2010). "CTLA-4 blockade: therapeutic potential in cancer treatments". Onco Targets Ther. 3: 15–25. doi:10.2147/ott.s4833. PMC 2895779. PMID 20616954.
- Robert C, Ghiringhelli F (August 2009). "What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma?". Oncologist. 14 (8): 848–61. doi:10.1634/theoncologist.2009-0028. PMID 19648604.
- Gail M. Wilkes; Margaret Barton-Burke (11 December 2009). 2010 oncology nursing drug handbook. Jones & Bartlett Learning. pp. 1–. ISBN 978-0-7637-8124-8. Retrieved 30 March 2011.
- L. Harivardhan Reddy; Patrick Couvreur (1 June 2009). Macromolecular Anticancer Therapeutics. Springer. pp. 522–. ISBN 978-1-4419-0506-2. Retrieved 30 March 2011.
- Zhiqiang An (8 September 2009). Therapeutic Monoclonal Antibodies: From Bench to Clinic. John Wiley and Sons. pp. 134–. ISBN 978-0-470-11791-0. Retrieved 30 March 2011.
- Ralph Blum; Mark Scholz (24 August 2010). Invasion of the Prostate Snatchers: No More Unnecessary Biopsies, Radical Treatment Or Loss of Sexual Potency. Other Press, LLC. pp. 227–. ISBN 978-1-59051-342-2. Retrieved 30 March 2011.
- Colmone, A. C. (2014). "Cancer immunotherapy expands T cell attack". Science. 345 (6203): 1463. doi:10.1126/science.345.6203.1463-c.
- Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (December 2017). "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. PMID 29208439.
- Gubin, Matthew M.; Schreiber, Robert D. (2015-10-09). "The odds of immunotherapy success". Science. 350 (6257): 158–159. doi:10.1126/science.aad4140. ISSN 0036-8075. PMID 26450194.
- Sharma, Pamanee; Allison, James P. (April 3, 2015). "The future of immune checkpoint therapy". Science. 348 (6230): 56–61. doi:10.1126/science.aaa8172. PMID 25838373. Retrieved June 2015. Check date values in:
- "CTLA-4 strategies: Abatacept / Belatacept". healthvalue.net. Retrieved 2009-06-24.
- Tomillero A, Moral MA (October 2008). "Gateways to clinical trials". Methods Find Exp Clin Pharmacol. 30 (8): 643–72. PMID 19088949.
- Poust J (December 2008). "Targeting metastatic melanoma". Am J Health Syst Pharm. 65 (24 Suppl 9): S9–S15. doi:10.2146/ajhp080461. PMID 19052265.
- "Top-Line Data Available from Three Ipilimumab Pivotal Trials in Patients with Advanced Metastatic Melanoma". Medarex, Inc. 2007-12-10. Archived from the original on October 20, 2008. Retrieved 2009-06-24.
- "Bristol drug cuts death risk in advanced melanoma". Reuters. 2010-06-05.
- Langreth R (2010-06-06). "The Risk For Bristol". Science Business - research, innovation & policy. Forbes. Archived from the original on 2011-03-15. Retrieved 2011-03-25.
- "Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against melanoma tumors". News-Medical.Net. 2010-06-09. Retrieved 2011-03-25.
- Silverman E (2010-06-07). "Bristol-Myers' Melanoma Med And Wall Street Wags // Pharmalot". Pharma Blog PHARMALOT. Archived from the original on 2012-09-08. Retrieved 2011-03-25.
- "'Surprise' prostate result probed". BBC News. 2009-06-19. Retrieved 2009-06-24.
- "Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study". Mayo Clinic. 2009-06-01. Retrieved 2009-06-24.
- Boyles S (2009-06-19). "New Therapy May Fight Prostate Cancer". WebMD. Retrieved 2009-06-24.
- Lowe, Derek (2009-06-23). "Medarex, Ipilimumab, Prostate Cancer, And Reality". Science Translational Medicine. Retrieved 2016-08-11.
- "Biomarker-Driven Therapy With Nivolumab and Ipilimumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Expressing AR-V7 - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-02-27.
- Silberstein, John L.; Taylor, Maritza N.; Antonarakis, Emmanuel S. (2016-02-23). "Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer". Current Urology Reports. 17 (4): 1–10. doi:10.1007/s11934-016-0584-4. ISSN 1527-2737. PMC 4888068. PMID 26902623.
- Antonarakis, Emmanuel S.; Lu, Changxue; Wang, Hao; Luber, Brandon; Nakazawa, Mary; Roeser, Jeffrey C.; Chen, Yan; Mohammad, Tabrez A.; Chen, Yidong (2014-09-11). "AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer". New England Journal of Medicine. 371 (11): 1028–1038. doi:10.1056/NEJMoa1315815. ISSN 0028-4793. PMC 4201502. PMID 25184630.
- "Impact of gemcitabine + cisplatin + ipilimumab on circulating immune cells in patients (pts) with metastatic urothelial cancer (mUC). - 2015 ASCO Annual Meeting - Abstracts - Meeting Library".
- pmhdev. "Immunotherapy drug combo could combat melanoma". PubMed Health.
- "A Two-arm, Single Center Phase 1b Trial of Bavituximab Plus Ipilimumab in Advanced Melanoma Patients". ClinicalTrials.gov.
- "Peregrine Pharmaceuticals Announces Initiation of an Investigator-Sponsored Trial Combining Its Immunotherapy Bavituximab and Ipilimumab (Yervoy®) in Advanced Melanoma". Peregrine Pharmaceuticals, Inc. Archived from the original on 2015-10-14. Retrieved 2014-05-20.
- "Data Presented at AACR Support Potential of Peregrine's PS-Targeting Immunotherapy Bavituximab to Enhance Anti-Tumor and Immune-Stimulating Effects of Anti-CTLA-4 and Anti-PD-1 Treatments in Models of Melanoma and Colon Cancer". Reuters. 2014-04-09. Retrieved 2014-04-09.
- Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (Jul 1987). "A new member of the immunoglobulin superfamily--CTLA-4". Nature. 328 (6127): 267–70. doi:10.1038/328267a0. PMID 3496540.
- Harper K, Balzano C, Rouvier E, Mattéi MG, Luciani MF, Golstein P (Aug 1991). "CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location". J Immunol. 147 (3): 1037–44. PMID 1713603.
- Harding F.; McArthur J.G.; Gross J.A.; Raulet D.H.; Allison J.P. (1992). "CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones". Nature. 356 (6370): 607–609. doi:10.1038/356607a0. PMID 1313950.
- Krummel, M.F. (1995). Identification and Characterization of a CTLA-4 Dependent Regulatory Mechanism for T Cell Activation (University of California, Berkeley).
- Krummel M.F.; Allison J.P. (1995). "CD28 and CTLA-4 deliver opposing signals which regulate the response of T cells to stimulation". Journal of Experimental Medicine. 182 (2): 459–465. doi:10.1084/jem.182.2.459. PMC 2192127. PMID 7543139.
- Krummel M.F.; Sullivan T.J.; Allison J.P. (1995). "Superantigen responses and costimulation: CD28 and CTLA-4 have opposing effects on T cell expansion In Vitro and In Vivo". International Immunol. 8: 101–105.
- Leach D.R.; Krummel M.F.; Allison J.P. (1996). "Enhancement of antitumor immunity by CTLA-4 blockade". Science. 271 (5256): 1734–1736. doi:10.1126/science.271.5256.1734. PMID 8596936.
- Walunas T.L.; Bakker C.Y.; Bluestone J.A. (1996). "CTLA-4 ligation blocks CD28-dependent T cell activation". Journal of Experimental Medicine. 183 (6): 2541–2550. doi:10.1084/jem.183.6.2541. PMC 2192609. PMID 8676075.
- Walunas T.L.; Lenschow D.J.; Bakker C.Y.; Linsley P.S.; Freeman G.J.; Green J.M.; Thompson C.B.; Bluestone J.A. (1994). "CTLA-4 can function as a negative regulator of T cell activation". Immunity. 1 (5): 405–413. doi:10.1016/1074-7613(94)90071-x. PMID 7882171.
- Kearney E.R.; Walunas T.L.; Karr R.W.; Morton P.A.; Loh D.Y.; Bluestone J.A.; Jenkins M.K. (1995). "Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4". J Immunol. 155: 1032–1036.
- Linsley P.S.; Greene J.L.; Tan P.; Bradshaw J.; Ledbetter J.A.; Anasetti C.; Damle N.K. (1992). "Coexpression and functional cooperativity of CTLA-4 and CD28 on activated T lymphocytes". Journal of Experimental Medicine. 176 (6): 1595–1604. doi:10.1084/jem.176.6.1595. PMC 2119471. PMID 1334116.