Modern cancer immunotherapy is the reemergence of an old field striving to use the body’s immune system to target cancer. Though cancer subverts the innate and adaptive immune systems, various non-cellular and cellu-lar based therapies have been developed to overcome these mechanisms. The variety of these techniques and their potential in the treatment of cancer has been a truly exciting development in medicine

England, Bryant

Karsy, Michael

English

The Touro College and University System

Quill & Scope Volume 6 Volume VI Article 7 2013 Cancer Immunotherapy Comes of Age Michael Karsy New York Medical College Bryant England New York Medical College Follow this and additional works at: https://touroscholar.touro.edu/quill_and_scope Recommended Citation Karsy, M., & England, B. (2013). Cancer Immunotherapy Comes of Age. Quill & Scope, 6 (1). Retrieved from This Perspective is brought to you for free and open access by the Students at Touro Scholar. It has been accepted for inclusion in Quill & Scope by an authorized editor of Touro Scholar. . For more information, please contact touro.scholar@touro.edu.  I magine training the body to attack cancer.  As de-fined by the National Cancer Institute, cancer is a process by which abnormal cells divide without control and are able to invade other tissues.1  This complex process is governed by genetic mutation, which results in cancer cells losing their resemblance to the normal cells they are ultimately derived from, overcoming built-in cellular mechanisms to prevent runaway growth, inducing neoangiogenesis or the formation of new blood vessels, as well as eventual metastasizing to foreign tissue sites.1  Importantly, cancers develop an ability to evade the body’s im-mune system through a variety of mechanisms, such as changing surface proteins that immune cells nor-mally use to home in on foreign cells, accumulation of regulatory T-cells (Treg) that suppress the immune response, as well as secretion of specific immune sig-naling cytokines (e.g., interleukin 6 [IL-6] and 10 [IL-10]) to inhibit lymphocytes that normally kill tumor cells.2,3  So if cancer has developed an ability to sub-vert the immune system, how is it possible to over-come this mechanism of tumor self-preservation?  The burgeoning field of immunotherapy may hold some answers in creating novel treatments for cancer as well as new ways of thinking about this old disease.  The immune system is a complexity overcome by the cleverness of cancer cells.  This system has been clas-sically divided into the innate and adaptive immune systems.2-4  The innate immune system is the first-line defense system involving anatomical barriers to infec-tion, cytokine-mediated recruitment of immune cells, as well as complement proteins, (molecules used to identify and destroy foreign cells while recruiting im-mune cells).  Other players in the innate immune sys-tem include macrophages that ingest and destroy for-eign cells, neutrophils that secrete destructive en-zymes, basophils and eosinophils that aid in eliminat-ing parasites, as well natural killer T-cells that target foreign cells, including tumor cells.  One of the ulti-mate results of the innate immune system is the acti-vation of the adaptive immune system via antigen presenting cells.  The adaptive immune system con-sists predominantly of CD8+ cytotoxic T-cells that mon-itor and destroy infected cells, CD4+ helper T-cells that identify foreign antigens to signal antibody produc-tion, and B-cells that are involved in sensing antigens and forming antibodies.  This system also includes gamma/delta T-cells that share characteristics of CD8+ and CD4+ T-cells.  Despite each of these intricate, well-regulated components, cancer cells have developed methods to overcome nearly every mechanism of the immune system.  Cancer immunotherapy is broadly defined as the abil-ity to induce the innate and adaptive immune system to neutralize neoplastic cells.  Multiple methods have developed over the past 50 years with the most inter-esting clinical applications unveiled only recently.  These include non-cellular methods such as antibod-ies and drugs to regulate the immune system (Figure 1) as well as cellular based techniques to manipulate the immune system such as adoptive cell transfer (ACT) and tumor vaccines (Figure 2).  These methods have shown mixed effects in different cancers again reaffirming the immense heterogeneity of cancer and difficulty in treating this disease.  A straightforward strategy to treat cancer includes inducing the immune system. Administration of the body’s own signaling molecules (cytokines such as IL-2 or interferon-α) has been shown to stimulate the immune system to fight cancer (Figure 1A).5  In fact, pegylated interferon-α2b was approved by the Feder-al Drug Administration (FDA) in 2011 for the treat-ment of melanoma.6  These initial approaches have been expanded by recent knowledge regarding im-mune-modulating antibodies and cell signaling.  Tu-mor-specific monoclonal antibody, generation is an approach that uses purified antibodies generated in the lab towards a specific tumor cell surface target.7 Rituximab (Biogen Idec/Genentech, San Francisco, CA) is a monoclonal antibody used to target CD20 cell re- Cancer Immunotherapy Comes of Age Michael Karsy & Bryant England 22        Quill & Scope 2012, Vol. 6 PERSPECTIVES  ceptors which has been approved by the FDA in the treatment of non-Hodgkin cell lymphoma and chronic lymphocytic leukemia, as well as several non-oncological diseases.8  Recent studies have surprising-ly shown that this antibody helps induce the immune system to kill targeted tumor cells in a process known as antibody-dependent cell-mediated cytotoxicity (ADCC) (Figure 1B).9  The drug Trastuzumab (Genentech, San Francisco, CA), also known as Her-ceptin and used to target the Her2/Neu growth factor receptor in the treatment of breast cancer, has also been shown to mediate ADCC in addition to its well known effects on altering growth factor signaling of targeted cancer cells.10  Other novel uses of monoclonal antibodies include immune-modulating antibodies.  Two new com-pounds, Ipilimumab (Bristol-Myers Squibb, Princeton, NJ) and Tremlimumab (Pfizer, New York, NY), have been shown to target CTLA-4 (Figure 1C)11.  Normally CTLA-4 is a co-regulatory receptor on T-cells that binds to molecules B7-1 and B7-2 found on dendritic or tumor cells and inhibits the immune system, which can allow cancer cells to escape targeting.  Ipili-mumab and Tremlimumab disrupt this inhibition and have shown response rates of 10-15% with metastatic melanoma and renal cell carcinoma.12  Ipilimumab has been FDA-approved as a first-line therapy for met-astatic melanoma based on promising phase III tri-als.13  Even newer therapies are looking at additional co-regulatory immune-checkpoint targets such as pro-grammed cell death 1 (PD1) which are present in many cancers and may result in a more universal on-Cancer Immunotherapy Comes of Age Quill & Scope 2013, Vol. 6        23  Figure 1: Non-cellular methods of immunotherapy. Various methods of immunotherapy using non-cellular means are shown.  A) Treatment with interleukin-2 (IL-2) or interferon-α can stimulate the immune system to fight cancer.  Examples include the use of pegylated interferon-α2b in the treatment of melanoma.  B) Designed tumor-specific monoclonal antibodies can target tumor cells via induction of an immune response (Antibody-mediated cell-dependent cytotoxicity) or via activation of the immune system’s complement cas-cade (Complement activation).  Examples include Rituximab for the treatment of non-Hodgkin cell lympho-ma and chronic lymphocytic leukemia as well as Trastuzumab in the treatment of breast cancer.  C) Im-mune-modulating antibodies are used to target co-regulatory proteins that allow T-cells to interact with tu-mor cells or antigen presenting cells.  Examples include Ipilimumab and Tremlimumab for the treatment of metastatic melanoma.  D) Antibody-drug conjugates and antibody-toxin conjugates are being developed to target tumor cells.  Antibody-radioisotope conjugates may allow for earlier tumor diagnosis.  Bispecific monoclonal antibodies are useful for localizing the body’s immune cells to tumor cells.  cological therapy.6,14 The ability of bifunctional anti-body-like molecules to bind cancer cells and retarget T-cells towards cancer cells (Figure 1D)15 or use anti-body-drug/antibody-toxin conjugates to directly target individual cancer cells (Figure 1D)16 is also an area of open investigation.  Antibody-radioisotope conjugates have also been investigated as methods to diagnose tumors earlier as well as identify disease progression sooner than current modalities.  These methods sug-gest that non-cellular based techniques to regulate the immune system can be potent ways of treating can-cer.   One form of immunotherapy that has gained momen-tum in recent years includes adoptive cell transfer (ACT).  This technique utilizes anti-tumor T-cells that are manipulated ex vivo and then infused into a pa-tient, in a similar method to bone marrow transplan-tation.  In one study, tumor infiltrating lymphocytes obtained from patients, expanded ex vivo in a lab, and then re-infused in patients with metastatic mela-noma showed that in addition to standard therapy, a clinical response of 34-72% was seen (Figure 2A).17  Therapies using such multicellular treatments have shown greater efficacy than therapy with purified sin-gle cells, again highlighting the heterogeneity of can-cers and their surface markers in striving to achieve personalized therapy.18  However, the limitation of ACT involves the cumbersome cell-extraction process.  Newer approaches utilize engineered T-cell receptors inserted into lab cultured CD4+ and CD8+ peripheral lymphocytes that can be transfused into patients.19  ACT can achieve tumor-inhibiting activity so long as a patient’s tumor possesses the required target.  Combi-nations of ACT treatments along with standard treat-ments are being investigated in various early phase clinical trials for some cancers.20  One of the most exciting avenues in immunotherapy is the development of cancer vaccines.  Initially set-Michael Karsy & Bryant England  24        Quill & Scope 2013, Vol. 6  Figure 2: Cell-based methods of immunotherapy towards cancers. Various methods of immunotherapy us-ing cellular means are shown. A) Adoptive cell transfer (ADT) is demonstrated.  Tumor infiltrating lympho-cytes are extracted from patients, expanded ex vivo in laboratory cultures, and reinfused back to patients.  Engineered T-cells can also be generated in cultures before reinfusion.  B) Cancer vaccines are shown.  Tu-mor cells are extracted from patients and specific tumor proteins are extracted before either being reinject-ed into patients or used to sensitize patient-derived dendritic cells to target tumors.   Examples include Spuleucel-T used in the treatment of hormone-resistant prostate cancer.  back by a variety of early clinical trial failures in the 1960s, this approach has generated renewed interest along with a recent FDA-approved treatment.  Cancer vaccines involve the administration of tumor proteins to generate an immune response or immune cells (i.e. dendritic cells) sensitized to tumor proteins (Figure 2B).  Spuleucel-T/Provenge (Dendreon, Seattle WA), FDA-approved in 2010 for the treatment of advanced hormone-resistant prostate cancer, involves inoculat-ing patient-derived peripheral blood mononuclear cells with prostatic acid phosphatase linked to granu-locyte macrophage colony-stimulating factor – essen-tially training a patient’s own cells to target prostate cancer specifically.21  In phase III trials, Spuleucel-T resulted in a 4-month overall survival benefit; The cost of this treatment, however, has been estimated to be approximately $100,000, which may limit its even-tual application.22  Vaccines towards melanoma23, high-grade glial24,25, breast26, pancreatic27, lung28 can-cers are currently in development.  New knowledge of immune regulation in cancer has improved the effica-cy of these approaches by using improved target anti-gens, high quantities of antigens to sensitize immuni-ty, and proper co-stimulatory signals to activate im-mune cells.  The field of immunotherapy is emerging significantly as a viable option in the treatment of cancer.  Much work has yet to be done before this dream can be-come a reality for many patients.  In addition, new developments have dramatically altered the concept that cancers have unilaterally circumvented the im-mune system.  Instead, various methods of inducing the immune system to fight cancer have been devel-oped, methods which will hopefully act as precursors for the development of similar methods in the near future.    REFERENCES 1] What Is Cancer? National Cancer Institute Availa-ble at: http://www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer. Accessed January 27, 2013. 2] Topalian SL, Weiner GJ, Pardoll DM. Cancer im-munotherapy comes of age. J. Clin. Oncol. 2011;29(36):4828–4836. 3] Mellman I, Coukos G, Dranoff G. Cancer immuno-therapy comes of age. Nature. 2011;480(7378):480–489. 4] Liu Y, Zeng G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J. Immunother. 2012;35(4):299–308. 5] Tarhini AA, Gogas H, Kirkwood JM. IFN-α in the treatment of melanoma. J. Immunol. 2012;189(8):3789–3793. 6] Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of can-cer in 2012. CA Cancer J Clin. 2012;62(5):309–335. 7] Reichert JM, Dhimolea E. The future of antibodies as cancer drugs. Drug Discov. Today. 2012;17(17-18):954–963. 8] Bauer K, Rancea M, Roloff V, et al. Rituximab, ofa-tumumab and other monoclonal anti-CD20 anti-bodies for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. 2012;11:CD008079. 9] Dall'Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: in-fluence of FCGR3A polymorphism on the concen-tration-effect relationship. Cancer Research. 2004;64(13):4664–4669. 10] Vu T, Claret FX. Trastuzumab: updated mecha-nisms of action and resistance in breast cancer. Front Oncol. 2012;2:62. 11] Sharpe AH, Freeman GJ. The B7-CD28 superfami-ly. Nat. Rev. Immunol. 2002;2(2):116–126. 12] Ribas A. Clinical development of the anti-CTLA-4 antibody tremelimumab. Seminars in Oncology. 2010;37(5):450–454. 13] Robert C, Thomas L, Bondarenko I, et al. Ipili-mumab plus dacarbazine for previously untreat-ed metastatic melanoma. N. Engl. J. Med. 2011;364(26):2517–2526. 14] Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a po-tential mechanism of immune evasion. Nat. Med. 2002;8(8):793–800. 15] Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blina-tumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J. Clin. On-col. 2011;29(18):2493–2498. 16] Younes A, Bartlett NL, Leonard JP, et al. 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The Lancet Oncology. 2012;13(7):e301–10.  26        Quill & Scope 2013, Vol. 6 Michael Karsy & Bryant England  

Cancer Immunotherapy Comes of Age

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Cancer Immunotherapy Comes of Age

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