Epidermal Growth Factor Receptor Plays a Critical Role in Malignancy in Targeted Therapy

Heather McCreery, RN, OCN^®, CCRC
San Antonio, TX
hmccreer@idd.org

A boom in translation research and discovery during the past 20 years has led to new classes of treatment agents aimed at key cellular mechanisms. We commonly refer to these as targeted agents because of their unique selectivity and affinity for specific activity in malignant cells. The ideal target is a pathway that is able to drive tumor growth and is responsible for key activities in the malignant cells. Targeted therapies strive to maintain healthy tissue through identification and interruption of key mechanisms.

Epidermal growth factor receptor (EGFR) is a family of four receptors, HER1 (ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Each receptor contains three domains: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. These receptors exist singularly but form pairs when activated (EGFR-Info.com, 2003). Ligand pairing (dimerization) activates intracellular tyrosine kinase (Wells, 1999). The activated tyrosine kinase then interacts with the ras protein which plays a crucial role in regulating cell growth and has been associated with mutated cellular proliferation (Jackson, n.d.). The ras protein then activates the mitogen-activated protein kinase (MAPK). MAPK delivers the signal to the nucleus where it interacts with the cyclin D molecule (Wells). MAPK interference results in accumulation of cyclin D. This excess of cyclin D allows the nucleus to override its resting phase and move into uncontrolled growth (Lundberg & Weinberg, 1999).

We know that activation of the EGFR results in uncontrolled cellular proliferation, but we also believe that EGFR-mediated signaling is responsible for other key cellular activities associated with malignancy. Although the exact mechanism remains under study, researchers believe that EGFR-mediated signaling results in limited apoptosis, the normal process by which dysfunctional cells are destroyed, thereby leading to increased volume of malignant cells (Karnes et al., 1998).

Investigators also believe that EGFR-mediated signaling plays a role in angiogenesis, the creation of blood vessels in tumors, by increasing angiogenic factors such as vascular endothelial growth factor. We don’t know the exact role of EGFR-mediated signaling in metastases, but we do know that EGFR is associated with increased incidence of metastases (Salomon, Brandt, Ciardiello, & Normanno, 1995).

Investigators have found overexpressed EGFR in a variety of solid tumors. Expressed or overexpressed EGFR is found in multiple human malignancies, including non-small cell lung cancer (NSCLC) and breast, head and neck, gastric, colorectal, esophageal, prostate, bladder, renal, pancreatic, and ovarian cancers (Salomon et al., 1995). EGFR also has been identified as a poor prognostic indicator, including time to treatment failure and shorter overall and progression-free survival (Poon et al., 2001; Salomon et al.).

Two mechanisms currently exist to inhibit EGFR: monoclonal antibodies and small molecule agents. Monoclonal antibodies target the external ligand-binding domain. Monoclonal antibodies that currently are in development and are directed specifically at EGFR include IMC-225, bevacizumab, and ABX-EGF. Small molecules inhibit EGFR via the intracellular tyrosine kinase pathway. Some examples of EGFR tyrosine kinase inhibitor agents currently in development are GW572016, OSI-774, and CI-1033. They possess the unique ability to inhibit all members of the EGFR family (Rinehart et al., 2003). The U.S. Food and Drug Administration recently approved Iressa™ (gefitinib, AstraZeneca Pharmaceuticals, Wilmington, DE) as a monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after the failure of both platinum-based and docetaxel chemotherapies (AstraZeneca Pharmaceuticals, 2003).

In studies with a variety of small molecule agents, investigators report rashes, most often maculopapular or acneiform in nature, as the most common adverse effect. These rashes also have been associated with pruritus. In studies with Iressa, investigators found skin rash to be dose related, whereas disease response was not (Gloss, 1995). In addition, some patients experienced disease responses without evidence of rash (Gloss). Although conflicts exist between reports of the correlation between rash and response, the presence of a rash is considered to be an important biologic marker (Gloss). Other small molecule adverse events include nausea, vomiting, diarrhea, and asthenia. The severity of nausea, vomiting, and diarrhea generally has been mild and only infrequently required interruption or reduction. In addition, doctors easily managed the symptoms with antiemetics and antidiarrheals. Continued development of agents targeted at EGFR promises a new treatment path for a variety of malignancies. As the U.S. Food and Drug Administration approves new agents that reach a large patient population, evidence-based nursing care will establish improved management of symptoms.

References
AstraZeneca Pharmaceuticals. (2003). About Iressa. First in a new class for NSCLC: An option where none existed before. Retrieved January 22, 2004, from http://www.iressa-us.com/content/prof/about

EGFR-Info.com. (2003). The epidermal growth factor as a clinical target in cancer. Retrieved October 4, 2003, from http://www.egfr-info.com

Gloss, G. (1995). WCLC conference highlights: Growing wealth of clinical experience with EGFR inhibitors. Signal, 4(3), 13–18.

Jackson, J. (n.d.). Specificity of ras signaling in breast cancer. Retrieved October 4, 2003, from http://www.cbcrp.org/research/PageGrant.asp?grant_id=1703

Karnes, W.E., Weller, S.G., Adjei, P.N., Kottke, T.J., Glenn, K.S., Gores G.J., et al. (1998). Inhibition of epidermal growth factor receptor kinase induces protease-dependent apoptosis in human colon cancer cells. Gastroenterology, 114, 930–939.

Lundberg, A.S., & Weinberg, R.A. (1999). Control of the cell cycle and apoptosis. European Journal of Cancer, 35, 1886–1894.

Poon, T.C.W., Chan A.T.C., To, K.F., Teo, P.M.L., Chan, M.L., Mo, K.F., et al. (2001). Expression and prognostic significance of epidermal growth factor receptor and HER2 protein in nasopharyngeal carcinoma [Abstract 913]. Proceedings of the American Society of Clinical Oncology, 20, 229a.

Rinehart, J.J., Wilding, G., Willson, J., Krishnamurthi, S., Natale, R., Dasse, K.D., et al. (2003). A phase I clinical and pharmacokinetic (PK)/food effect study of oral CI-1033, a pan-erb B tyrosine kinase inhibitor, in patients with advanced solid tumors [Abstract 821]. Proceedings of the American Society of Clinical Oncology, 22, 205.

Salomon, D.S., Brandt, R., Ciardiello, F., & Normanno, N. (1995). Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology and Hematology, 19, 183–232.

Wells, A. (1999). Molecules in focus EGF receptor. International Journal of Biochemistry and Cell Biology, 31, 637–643.

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National Cancer Institute Tests New Developments in Immunotherapy

Leah Haworth, RN, BSN
Gaithersburg, MD
haworthl@mail.cc.nih.gov

Immunotherapy treats cancer by using portions of the body’s natural immune system to fight the disease. Immunotherapies such as monoclonal antibodies, interferon, and interleukin-2 have become standard treatment for several types of cancer. The immune system, the body’s defense against foreign and damaged cells, contains mechanisms that help to distinguish between “self” and “nonself” cells to prevent the occurrence of autoimmunity. Autoimmunity occurs when the immune system attacks normal tissue in the body. Cancerous tumor cells often escape the attack of the immune system because they are not identified as being nonself. However, several types of cancer are immunogenic, meaning they have markers on the surface of cells (i.e., antigens) that can be identified by the immune system. Therefore, immunotherapy can treat these types of cancer, such as melanoma and renal cell carcinoma.

New Antibody Therapy
Steven Rosenberg, MD, chief of surgery at the National Cancer Institute (NCI), is testing a new approach to immunotherapy using a monoclonal antibody called anticytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4). CTLA-4 has been recognized as a marker on the surface of T-lymphocytes that serves to down-regulate or turn-off the T-cells to prevent them from overreacting and damaging normal tissues. For example, when we are infected with a cold virus, our immune systems respond by sending immune cells to attack the foreign invaders that have been identified as nonself inside the body. Once the immune system eradicates these foreign invaders and controls the infection, the CTLA-4 molecule appears to act as the off switch to the immune response. The new anti-CTLA-4 antibody acts by blocking the activity of this critical off switch, thereby maintaining the reactivity of the T-lymphocytes.

In 2003, Rosenberg’s team at NCI began a trial combining anti-CTLA-4 with two melanoma gp100 peptide vaccines for the treatment of patients with metastatic melanoma (Phan et al., 2003). The gp100 peptides are vaccines synthesized in the laboratory that are derived from known melanoma tumor antigens that can be identified by the immune system. Investigators have given these vaccines to patients in previous NIH studies and have seen little or no tumor responses (Rosenberg et al., 1998). The theory behind this new combination treatment of anti-CTLA-4 plus gp100 peptides, as explained to patients, is that the gp100 stimulates T-lymphocytes to react against melanoma tumor antigens and the anti-CTLA-4 helps sustain the reactivity of the activated T-lymphocytes, increasing the immune response against melanoma.

Patients in this trial received an IV infusion of anti-CTLA-4 followed by subcutaneous injections of two different gp100 melanoma peptide vaccines, repeated every three weeks. Fourteen patients initially were treated using this regimen, administering the anti-CTLA4 at a dose of 3 mg/kg. Investigators saw several toxicities within the first few months of the study. These toxicities were autoimmune in nature, meaning the immune system was attacking normal tissue. Two patients developed autoimmune colitis (i.e., inflammation of the colon) that caused severe diarrhea. Three patients developed a generalized rash and itching over more than 50% of their body surface area. One patient developed autoimmune hepatitis (i.e., severe inflammation of the liver). Another patient developed autoimmune inflammation of the pituitary gland that caused the gland to cease normal functioning. Investigators treated many of the patients’ severe autoimmune side effects with steroid therapy. Steroids suppress the immune system, and doctors generally will not prescribe them to a patient undergoing immunotherapy unless the toxicity is potentially life threatening.

Three of the 14 patients experienced an objective tumor response, meaning that the total amount of tumor decreased by at least 50%. Two of the three responders had a complete disappearance of all tumors. Interestingly, all three of these responders also experienced at least one of the autoimmune toxicities. The patient who experienced the pituitary gland inflammation first began treatment with more than 30 lung tumors, a brain tumor, and a subcutaneous tumor. After receiving four doses of anti-CTLA-4 plus gp100 peptide vaccines, he had a complete disappearance of all tumors at which time the pituitary abnormalities also became apparent. The patient started oral medications to replace the hormones that his pituitary gland was no longer producing. The patient’s symptoms resolved, and he has been without evidence of melanoma for more than nine months.

Anticytotoxic T-Lymphocyte-Associated Antigen-4 Dose Lowered
Because of the toxicities observed in the first 14 patients, investigators treated a second group of patients with a lower dose of anti-CTLA-4. They gave 27 patients the lower dose, consisting of a 3 mg/kg loading dose of anti-CTLA-4 plus gp100 peptides, followed by a 1 mg/kg dose plus peptides repeated every three weeks. Four of the 27 patients have experienced severe autoimmune toxicities, including pruritic rash covering more than 50% of the body surface area, colitis resulting in more than six stools a day and requiring the need for parental support for dehydration, and inflammation of the eye causing decreased vision. Three patients experienced an objective tumor response. Two of the three patients evidencing a tumor response also experienced severe autoimmune toxicities.

Autoimmunity and Tumor Response
Investigators have learned thus far that an objective tumor response correlates highly with autoimmunity. Fifty percent of all patients who experienced severe autoimmunity also experienced an objective tumor response. Five of the six patients who experienced an objective tumor response experienced severe autoimmune toxicities. Interestingly, the one patient who exhibited a tumor response but did not experience severe autoimmune toxicity is the only patient who has had a tumor recurrence to date. The CTLA-4 marker, which normally is found on the surface of T-lymphocytes, appears to play a critical role in regulation of the immune system and the body’s ability to distinguish between self and nonself. By disabling this T-lymphocyte off switch with anti-CTLA-4, the CTLA-4 marker appears to unleash the immune system and direct it against melanoma tumors. However, this immune stimulation appears to result in reactivity against normal cells as well, resulting in autoimmune toxicities.

All autoimmune toxicities experienced by the patients participating in this study were resolved once treatment with anti-CTLA-4 was discontinued; most occurrences of severe autoimmunity required treatment with steroids. Of the six patients who experienced a tumor response on the anti-CTLA-4 protocol, three received treatment with steroids for autoimmunity. None of the three responders who received immunosuppressive steroids to treat autoimmune toxicities have experienced progression of their melanoma to date since beginning anti-CTLA-4 therapy. Thus, steroid therapy does not appear to limit the potential activity of anti-CTLA-4 to mediate cancer regression.

Biopsies of the skin, colon, and liver in patients who exhibited autoimmune toxicities in these organs showed significant amounts of cancer-fighting immune cells, called T-lymphocytes. In addition, a biopsy taken of a melanoma tumor from a patient evidencing a tumor response showed a massive amount of T-lymphocytes. In fact, the melanoma tumor was so full of lymphocytes that the pathologist initially believed the tumor was a lymph node.

Conclusions and Future Plans
Analysis of these 41 patients showed that the group that received the higher dose of anti-CTLA-4 (the 14 patients who received repeated doses at 3 mg/kg) experienced severe autoimmune toxicities at a rate that was approximately twice that seen in the group that received the lowered dose regimen (the 27 patients who received a 3 mg/kg loading dose of anti-CTLA-4 followed by repeated doses at 1 mg/kg). However, doctors also noted that the percentage of tumor responses in the patients who received the higher dose regimen was approximately twice that seen in the group of patients who received the lowered dose. Plans currently are being made to return to the higher 3 mg/kg dose level of anti-CTLA-4 on the study because it appears to produce a higher tumor response rate and the autoimmune toxicities can be controlled safely with support medications and/or steroids. Rosenberg and his team are planning a new study, in which individual patients will receive escalating doses of anti-CTLA-4 until either a tumor response and/or severe autoimmunity is achieved.

Nursing Implications
Anti-CTLA-4 is administered by IV during a period of 90 minutes. Investigators have observed no immediate side effects during antibody administration in the 41 patients treated thus far. The two gp100 peptide vaccines are administered subcutaneously in both thighs. Patients receive each peptide, divided into two injections of 1 ml each, within 1 cm of each other. If a patient has undergone a previous lymph node dissection in either groin, the vaccine is given in an upper extremity instead. The peptide vaccines generally produce inflammation at the injection site. Patients often experience mild to moderate redness, swelling, itching, and sometimes pain at the injection sites. These reactions generally are tolerated well and resolve over time. If patients find the symptoms bothersome, they should apply cold or warm compresses to the injection sites and take oral nonsteroidal anti-inflammatories such as acetaminophen or ibuprofen and oral antihistamines such as diphenhydramine and hydroxyzine.

Autoimmune toxicities generally do not appear earlier than one week after the first treatment. Patients typically experience the first signs of side effects at home; therefore, outpatient symptom management is critical. Patient education at the time of the first treatment about potential symptoms and side effects is very important. Rashes are managed with oral and topical antihistamines, and colloidal oatmeal baths may provide symptomatic relief. Severe diarrhea (> 6 stools per day) usually requires hospital admission to manage fluid replacement requirements. Patients are placed on bowel rest and administered IV hydration. Colonoscopy and upper endoscopy may be performed to confirm active colitis and inflammation, and steroids are given if the diarrhea continues despite conservative management.

Additional Studies Using Anticytotoxic T-Lymphocyte-Associated Antigen-4
Rosenberg and his team recently implemented two additional studies at NCI using anti-CTLA-4. The first, for patients with metastatic melanoma, combines interleukin-2 with escalating doses of anti-CTLA-4. Interleukin-2 is a standard approved immunotherapy treatment for melanoma with an established tumor response rate of approximately 15%. The rationale for this study is that by combining anti-CTLA-4 and interleukin-2, an immune response can be mounted against melanoma and result in a tumor response. NCI recently began a second study focusing on patients with renal cell carcinoma, another type of cancer that can be recognized by the immune system. Investigators have seen responses in patients on both of these studies thus far, and both studies continue to enroll new patients.

References
Phan, G.Q., Yang, J.C., Sherry, R.M., Hwu, P., Topalian, S.L., Schwartzentruber, D.J., et al. (2003). Cancer regression and autoimmunity induced by cytotoxic T-lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proceedings of the National Academy of Science, 100, 8372–8377.

Rosenberg, S.A., Yang, J.C., Schwartzentruber, D.J., Hwu, P., Marincola, F.M., Topalian, S.L., et al. (1998). Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nature Medicine, 4, 321–327.

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SIG Members Present on Targeted and Molecular Therapies at the Institutes of Learning

Paula Muehlbauer, RN, MSN, OCN^®
Alexandria, VA
pmuehlbauer@mail.cc.nih.gov

Targeted and Biological Therapies SIG members presented “Emerging World of Targeted and Molecular Therapies” at the ONS Fourth Annual Institutes of Learning in Philadelphia, PA, in November 2003. MaryAnn Dyky, MSN, ACNP-BC, AOCN^®, laid the groundwork by reviewing cancer pathophysiology, including molecular cancer biology, and I gave updates about cancer antiangiogenic agents and cancer vaccines. Laura Wood, RN, MSN, OCN^®, reviewed the emerging drug concept of the role of cytochrome p450. She also enlightened all about the proteasome pathway and inhibitors as well as antisense therapy. ONS recorded the session, which can be viewed on the ONS Web site (www.ons.org).

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Seminars in Oncology Nursing Highlights Targeted and Biologic Therapies

Debbie Parchen, RN, OCN^®
Gaithersburg, MD
dparchen@mail.cc.nih.gov


For those nurses looking for a variety of up-to-date articles about targeted and biological therapies, the August 2003 edition of Seminars in Oncology Nursing (Vol. 19, No. 3) has it. Novice nurses and clinical specialists will find the information suitable. Some topics include emerging therapies, molecular biology and immunology, monoclonal antibodies, anti-angiogenesis, and molecular targets. Our own Targeted and Biological Therapies SIG Coordinator-Elect Paula Muehlbauer, RN, MSN, OCN^®, wrote one article titled “Anti-Angiogenesis in Cancer Therapy.”

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SIG Welcomes New Members


The Targeted and Biological Therapies SIG would like to tip its hat to those who have become members since September 2003.

Rita M. Battaglini, RN, BSN, OCN^®
Theresa W. Gillespie, PhD, BA, BSN, MA, RN
Carolyn S. Hendrix, RN, OCN^®
Susan E. King, RN, MS, OCN^®
Marilyn Klocksiem, RN, BSN, OCN^®
Linda A. Koppenaal, RN, BSN, OCN^®

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Targeted and Biological Therapies SIG Officers

Coordinator Peg Esper, MSN, RN, CS, AOCN® 1755 Ridgewood Ln. Commerce Township, MI 48382-4830 248-363-8414 (H) 734-615-4082 (fax) pesper@umich.edu Coordinator-Elect Paula Muehlbauer, RN, MSN, OCN® 3733 Jason Ave. Alexandria, VA 22302-1811 703-845-3442 (H) 734-615-4082 (fax) pmuehlbauer@mail.cc.nih.gov

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