The Washington Manual of Oncology, 3 Ed.

Cancer Immunotherapy

Gerald P. Linette • Beatriz M. Carreno

 I. DEFINITION. Cancer immunotherapy is based on the principle that a patient’s own immune system can be harnessed to reject a malignant tumor. The decade of the 1980s was arguably the beginning of modern human cancer immunotherapy. Prior to the 1980s, astute clinicians reported sporadic cases of cancer regression in patients exposed to infectious pathogens (either deliberately or by natural infection); however, mechanistic insights were minimal and skepticism prevailed. Fundamental discoveries on how the immune system recognizes and eliminates pathogens, a deeper understanding on how the innate and adaptive immune system can be modulated to eliminate neoplastic cells, and the development of humanized monoclonal antibodies provided the necessary foundation to develop rational approaches for cancer immunotherapy.

 Multiple modalities of cancer immunotherapy are currently in the clinic or under development, including cytokines (systemic therapy); antibody-based (targeting cell surface molecules in cancer and immune cells), cellular therapies (DC vaccines and T/NK cell therapies), and gene transfer viral vectors (virus-mediated tumor-directed immunity). Collectively, these therapeutic modalities represent a paradigm shift in cancer treatment by targeting the immune system instead of the cancer cell and have coalesced into a burgeoning and credible discipline that offers tremendous potential to solidify its position as the fourth major modality of cancer treatment.

 Importantly, the complexity of tumors cannot be overlooked, from the heterogeneity of the cancer genome to its dynamic relationship with the tumor microenvironment. It is now apparent that cancer immunotherapy will require the addition of other modalities (such as targeted agents or cytotoxic drugs) to promote optimal benefit in patients with advanced or metastatic disease. This chapter will focus on human cancer immunotherapy, emphasizing the agents and modalities that will likely be incorporated into the practice of oncology—some are FDA-approved drugs, and others are investigational therapies that have shown considerable activity in clinical trials.

1. THE IMMUNE SYSTEM
2. The innate system. Innate immunity is the first line of host defense that is activated upon initial encounter with infectious pathogens such as bacteria, fungi, parasites, and viruses. Innate immunity is defined by host pattern recognition receptors (PRR) that bind conserved pathogen-associated molecular pattern (PAMP) domains encoded by infectious pathogens. A variety of PAMP domains have been characterized including lipopolysaccharide, double/single stranded viral nucleic acid as well as β-1,3–linked glucan. Several PRR families have been identified including toll-like receptors (TLRs), NOD-like receptors (NLRs), retinoic acid-inducible gene-1 (RIG-1) receptors, and C-type lectin receptors. The key attribute of the various PRR families is signal transduction to activate the production of proinflammatory cytokines such as IL-1β, IL-12, TNF-α, and type-1 interferon. There are also dedicated “innate” receptors that serve to promote the process of phagocytosis such as the mannose receptors expressed on macrophages. Major cell types of the innate immune system include granulocytes, mast cells, macrophages, dendritic cells (DC), and natural killer (NK) cells. NK cells mediate immediate/short-lived (cytotoxicity or cytokine release) responses and play a critical role in tumor surveillance. DCs play a crucial role as professional antigen-presenting cells (APC) that capture and process antigen to initiate T cell immunity.
3. The adaptive system. Three features define adaptive immunity: diversity, specificity, and memory. Major cell types of the adaptive immune system are B lymphocytes that carry out humoral immunity and T lymphocytes that carry out cell-mediated immunity. B and T lymphocytes utilize a process of somatic recombination to generate the highly diverse repertoire of antigen receptors required for recognition of foreign pathogens and neoplastic cells (i.e., antigens). A central tenet of adaptive immunity is the clonal selection theory as proposed by Burnet and Talmage in 1957, which suggested that antigen stimulates specific lymphocyte clones through their antigen receptors, surface immunoglobulin for B lymphocytes, and T cell receptors (TCR) for T lymphocytes, to undergo mitosis, expand, and differentiate into effector cells. After the antigen (pathogen) is cleared, the lymphocytes die by apoptosis and a pool of “memory” lymphocytes survive to protect the host upon antigen re-exposure. Immunologic memory—both humoral and cellular—can last for decades. Antigen specificity is dictated principally by defined regions (CDR3 loops) contained within antibodies and TCRs. Two lineages (αβ TCR and γδ TCR) of T cell lymphocytes mediate cellular immunity. αβ T lymphocytes are further subdivided into two major subsets, the CD4+ (helper) T cells and CD8+ (cytotoxic) T cells. Regulatory T cells often defined by the CD4+CD25+FoxP3+ phenotype infiltrate most tumor sites and are regarded as a significant barrier to effective tumor immunity. Newly characterized cell types that bear rearranged TCRs include invariant type 1 NKT cells, type 2 NKT cells, and mucosal invariant T cells that appear to play a role in the recognition of infectious pathogens; as such, their role in the tumor immune response is less well defined.

 III. THERAPEUTIC MODALITIES

1. Cytokines. Cytokines are small proteins (5 to 20 kDa) that play an important role in cell-to-cell communication. They stimulate immunity by targeting cells that express the appropriate receptors and are important modulators of innate and adaptive immune responses.
2. Interferon alpha. The first biologic cancer therapy produced by recombinant DNA technology in the early 1980s. Interferon Alpha is a member of a family of related proteins made by white blood cells that regulate immune responses and inflammation; in addition, interferon Alpha can also interfere with virus replication and, accordingly, are used to treat certain chronic viral infections. There are two closely related types of interferon Alpha that are approved for use in cancer patients. Interferon Alpha 2a (Roferon-A) is approved for CML, hairy cell leukemia, AIDS-related Kaposi’s sarcoma as well as chronic hepatitis C. Interferon Alpha 2b (Intron A) is used as adjuvant treatment of high-risk resected melanoma as well as condylomata acuminata, AIDS-related Kaposi’s sarcoma, chronic hepatitis C, and chronic hepatitis B. Both cytokines are available as pegylated versions. Interferon Alpha n3 (Alferon-N, Hemispherx Biopharma) is approved for the treatment of genital and perianal warts caused by human papillomavirus (HPV). Other interferons (such as Interferon Beta and Interferon Gamma) are used for nononcology indications.
3. Interleukin-2. An important growth factor/activator of T cells and NK cells, developed in the 1980s, it is indicated for the treatment of renal cell carcinoma and metastatic melanoma. In view of the side effects and potential toxicities, high-dose IL-2 (600,000 to 720,000 IU/Kg/dose intravenously) (Proleukin) should be restricted to use in selected patients and administered in the hospital setting by an experienced oncologist.
4. Investigational cytokines. IL-7, IL-12, IL-15, and IL-21 are currently in early to midstage development in oncology primarily as mediators of T lymphocytes activation and homeostasis. Many clinical trials are focused on the use of cytokines in conjunction with cancer vaccines and adoptive T cell/NK cell therapies to enhance antitumor immunity.
5. Antibody-based therapies. The landmark development of monoclonal antibodies (mAbs) by Kohler and Milstein in 1975 laid the foundation for the use of antibodies in oncology; however, the full therapeutic potential of these agents remained unfulfilled until the process of antibody humanization was described in the 1980s.
6. Immune checkpoint blockade. T cell activation is dependent upon signals delivered through the antigen-specific TCR and accessory receptors. These accessory receptors do not function independently, but serve to enhance or inhibit TCR-mediated signals. CTLA-4 (cytotoxic T lymphocyte antigen-4) and PD-1 (program death-1) are accessory receptors expressed on activated T cells that act as negative regulators to dampen T cell responses. “Immune Checkpoint Blockade,” in general, refers to a therapeutic approach that uses antagonistic CTLA-4- or PD-1/PD-L1-targeted antibodies to increase T cell immunity.
7. Anti-CTLA-4 (CD152) antibodies

 i. Ipilimumab (Yervoy) is a humanized mAb (IgG1) that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86 (expressed on immune cells, primarily antigen-presenting cells). This blockade overcomes the T cell inhibitory pathways elicited by CTLA-4 signaling, effectively enhancing T cell proliferation. Ipilimumab is indicated for the treatment of patients with unresectable or metastatic melanoma and was granted regulatory approval in March 2011. Ipilimumab has been shown to prolong overall survival in patients with metastatic melanoma (N Engl J Med 2010;363:711).

A major issue related to the use of ipilimumab is the risk of immune-related adverse events. Treating physicians must be able to recognize, diagnose, and treat potential autoimmune-related toxicities, which are unique and distinct from the common toxicities seen with conventional cytotoxic agents and targeted kinase inhibitors. Immune-related adverse events such as rash, diarrhea, colitis, autoimmune hepatitis, endocrinopathy (hypophysitis), and peripheral neuropathy are frequently observed (J Clin Oncol 2012;30:2691). A Risk Evaluation and Mitigation Strategy is an important component of educating both physicians and patients on the immune-mediated adverse reactions unique to ipilimumab (Yervoy) administration in patients.

  ii. Tremelimumab (AstraZeneca) is a humanized mAb (IgG2) directed against CTLA-4 with a mechanism of action similar to ipilimumab. It was tested in a phase 3 randomized clinical trial in metastatic melanoma but failed to demonstrate superior clinical activity compared with dacarbazine (J Clin Oncol 2013;31:616). The safety profile of tremelimumab appears to be similar to that of ipilimumab. Clinical trials with this agent for various oncology indications are ongoing.

1. Anti-PD-1 (CD279)/PD-L1 (CD274) antibodies. PD-1 is expressed on the surface of activated T cells and when bound by its ligands (PD-L1 and PD-L2) acts to transduce a negative signal to modulate T cell activation after TCR engagement. Among PD-1 ligands, PD-L1 is of particular interest given that it is expressed on the cell surface of various neoplasms, including melanoma, non–small cell lung carcinoma, and renal cell carcinoma. Thus, the PD-1: PD-L1 interaction appears to downregulate T cell function and effectively impairs tumor recognition by activated T cells within the tumor microenvironment. Antagonistic antibodies directed at either PD-1 or PD-L1 are being tested in clinical trials in a wide variety of malignancies and the data from phase 1 and phase 2 clinical trials is very encouraging with response rates ranging from 10-40% in solid tumors (N Engl J Med 2012; 366: 244, N Engl J Med 2012; 366: 2455, N Engl J Med 2013; 369: 134). FDA approval for anti-PD-1 mAb (Pembrolizumab) was granted in September 2014 for treatment of patients with advanced or unresectable melanoma after BRAF inhibitor and ipilimumab. Regulatory approval of additional anti-PD-1 (Nivolumab) and anti-PD-L1 (MPDL3280A) mAbs is anticipated in 2015 and beyond. Although immune-related adverse events are seen with anti-PD-1 and anti-PD-L1 mAbs, the rate and severity appear to be lower when compared with that reported for ipilimumab. The combination of ipilimumab with nivolumab is under investigation in patients with metastatic melanoma (N Engl J Med 2013;369:122).

 Given the clinical benefit demonstrated by targeting CTLA-4 and PD-1/PD-L1, mAbs directed at other checkpoint molecules (OX-40, GITR, CD137, LAG-3, and TIM-3) are under development for the treatment of multiple malignancies.

2. Dual-targeting agents. Dual-targeting agents act, in most instances, as a bridge between distinct cell types promoting immune cell-mediated tumor destruction.
3. Bispecific antibodies are agents that combine the antigen-recognition sites of two antibodies within a single antibody molecule (150 kDa).

 Catumaxomab (Removab) is a bispecific rat–mouse hybrid mAb directed against CD3, the signaling complex on T lymphocytes, and EpCAM, an epithelial cell surface antigen present on several malignancies. Catumaxomab is indicated for treatment of malignant ascites. Catumaxomab is approved only for use in the EU as of April 2014.

1. Bispecific T cell Engagers (BiTES) and dual affinity retargeting proteins (DARTS) are ~50 kDa molecular entities that combine the antigen-recognition sites of two antibodies. Most frequently, one of the antigen-recognition sites is directed against CD3, while the other targets a tumor-specific molecule. In BiTES, both recognition sites are presented on a single polypeptide. In DARTS, separate polypeptides linked via disulfide bridges combine to make two antigen-recognition sites.

 i. Blinatumomab (Amgen) is an anti-CD19 × anti-CD3 BiTE in development for Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin’s Lymphoma (NHL)..

  ii. MGD006 (Macrogenics) is an anti-CD123 × anti-CD3 DART in development for AML.

1. Immune mobilizing mTCR Against Cancer (ImmTACs) are of similar molecular weight to BiTES and DARTS, but these entities combine an antigen-recognition site directed at CD3 and a soluble, high-affinity TCR specific for a tumor (peptide) antigen/MHC complex.

 IMCgp100 (Immunocore) is an anti-CD3 × YLEPGPVTA /HLA-A*02:01-specific TCR in development for melanoma.

1. Cancer vaccines. Broadly speaking, there are two categories of cancer vaccines. Prophylactic cancer vaccines are intended to prevent cancer in high-risk populations, while therapeutic vaccines are designed to treat existing malignancies.
2. Prophylactic cancer vaccines. There are two indications for which vaccines have been shown to reduce the incidence of viral infections that are associated with cancer: Hepatitis B virus (HBV) and Human Papilloma Virus (HPV). On the basis of a 20-year follow-up, the HBV vaccine has been proven to lower the incidence of hepatocellular carcinoma in children and young adults in Taiwan. Since the HPV vaccine was approved in 2006, additional follow-up is needed before a definitive assessment can be made regarding its impact on the incidence of cervical cancer.
3. HBV. Hepatitis B is a DNA virus that infects the liver and can cause both acute and chronic disease. It can be transmitted through blood, bodily fluids (intimate contact), and the maternal–fetal route. Most individuals that are infected can clear the virus within 6 months; however, approximately 3% of immunocompetent adults become chronic carriers and are at substantial (15% to 25% chance) risk of developing cirrhosis and/or hepatocellular carcinoma. High-risk groups that are more prone to develop chronic HBV infection include newborn infants, children infected before the age of six, and HIV-infected individuals. According to the World Health Organization, there are more than 240 million people worldwide with chronic liver infections. It is estimated that 600,000 people die each year due to HBV. Prevalence rates for HBV infection are highest in sub-Saharan Africa and East Asia (5% to 10% adults chronically infected), moderate in the Amazon, Eastern/Central Europe, Middle East, and lowest in Western Europe and North America (<1%). Mother-to-child transmission at birth is common in highly endemic areas.

 i. HBV vaccine. The HBV subunit vaccine was approved in 1981. The initial formulation used HBV surface antigen (HBsAg) purified and inactivated from the plasma of infected individuals. A recombinant HBsAg derived vaccine was approved in 1986 and remains in current use as the standard formulation. Universal infant vaccination in the United States began in 1991, while adolescent vaccinations began in 1996. Three vaccine doses are typically administered over a 6-month period. In most vaccinated healthy individuals, immunity is lifelong, and booster vaccine doses are not normally suggested. The current vaccine induces protective antibody levels in >95% of infants, children, and young adults. The rate of protective immunity declines with age (>40 years), concurrent HIV infection, and certain comorbid illnesses such as diabetes and renal failure.

1. HPV. Human Papilloma virus is a DNA sexually transmitted virus that causes genital warts. It is estimated that HPV causes approximately 5% of all cancers in men and 10% in women—most notably anogenital cancers and oropharyngeal carcinoma. Of the more than 100 HPV genotypes, 15 are considered high-risk mucosatropic types associated with cancer. HPV 16 and 18 are considered the most prevalent high-risk types that are associated with cancer, while HPV 6 and 11 are low-risk types often associated with genital warts. HPV 16 and 18 are detected in approximately 70% of all cervical cancer cases worldwide, with the rest associated with the remaining high-risk HPV genotypes.

 i. HPV vaccine. The first HPV subunit vaccine was approved in 2006. There are two formulations in use in the United States. Gardasil quadrivalent formulation contains the yeast-derived major capsid L1 protein of HPV types 6, 11, 16, and 18 emulsified in aluminum hydroxyphosphate sulfate as adjuvant. Cervarix bivalent formulation contains the yeast-derived major capsid L1 protein of HPV types 16 and 18 emulsified in aluminum hydroxide and monophosphoryl lipid A. According to current CDC guidelines, HPV vaccines are recommended for preteen girls and boys starting at age 11 to 12 years. HPV vaccination is highly efficacious in preventing the development of persistent vaccine-type HPV infections and associated intraepithelial neoplasia in both females and males (Nature Reviews. Clin. Oncology 2013;10:400). Interestingly, the quadrivalent HPV vaccine protects against nonvaccine HPV type 31, while the cross-protective efficacy of the bivalent vaccine extends to HPV types 31, 33, 45, and 51.

2. Therapeutic cancer vaccines. Sipuleucel-T (Provenge, Dendreon) is an autologous cellular product indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer and was FDA-approved in 2010. The active components of sipuleucel-T are autologous APCs and the polyprotein PAP-GM-CSF (Prostate acid phosphatase/granulocyte macrophage colony-stimulating agent). Other cell types (T cells, B cells, NK cells) are included in the cell product, which is administered in 250 ml of Lactated Ringer’s solution. Sipuleucel-T is administered intravenously in a three-dose schedule at approximately 2-week intervals. Each dose given as a 60-minute infusion contains a minimum of 50 million CD54+ APCs loaded with PAP-GM-CSF protein. Sipuleucel-T increases overall survival by 4 months compared with placebo infusions (25.8 m vs. 21.4 m, p=0.032, HR0.775) (N Engl J Med 2010;363:411).
3. Adoptive cell therapies
4. T cell therapies. T cell therapy is currently the focus of intense scientific interest in early stage clinical development. Donor lymphocyte infusions (DLI) are considered in this section despite the fact that most DLI products are not manipulated prior to infusion. Virtually all other T cell products are manipulated by in vitro culture and in many instances genetically modified using viral vectors. T cell retargeting with antigen-receptor gene therapy via viral vectors is the current focus of much of the research.
5. Donor lymphocyte infusion (DLI). Patients that relapse after an allogeneic bone marrow transplant can be given an infusion of bulk or purified lymphocytes from the donor in order to induce a remission. In relapsed CML after allogeneic transplant, DLI induces long-term remissions in >50% of patients. The potential risks include graft-versus-host disease and bone marrow aplasia.
6. Tumor infiltrating lymphocytes (TIL). Metastatic deposits of melanoma are infiltrated by a variety of immune-related cells, including T cells that are specific for the tumor. Surgical resection of tumor metastases allows the isolation and subsequent propagation of the T cells in culture for ex vivo expansion in the presence of IL-2. TIL consists of a mixture of CD4+ and CD8+ T lymphocytes; however, in most instances, the fine antigen specificity of TIL remains unknown. A course of high doses of IL-2 (720,000 IU/kg q 8h) is given with infused T cells. Response rates range from 40% to 70%, and 10% to 20% responses can be durable (Clin Cancer Res 2011;17:4550).
7. Chimeric antigen receptor (CAR). Engineered antigen-targeting receptors that are genetically inserted into patient effector T lymphocytes for adoptive transfer. The most common form of antigen-targeting receptors is single-chain variable fragments (scFv) derived from monoclonal antibodies specific for cell surface tumor antigens such as CD19, a molecule expressed on a variety of hematologic malignancies. The scFv is fused to a transmembrane/signaling module that typically encodes either the co-stimulatory CD28 or CD137 domain coupled to the TCR signaling (CD3ζ) domain. CAR T cell adoptive therapy directed against CD19 is especially promising with early phase 1 results from multiple centers documenting response rates >50% in adult Chronic Lymphoblastic Leukemia (CLL)/ALL and pediatric ALL. Durable complete remissions beyond 3 years have been reported in adult CLL patients given a single T cell infusion.
8. TCR gene therapy. Engineered TCR are genetically inserted into patient effector T lymphocytes for adoptive cell transfer. In principle, the TCR are modified to create higher affinity receptors to recognize the antigenic peptide-MHC complex present on tumor cells. Pilot human trials with the NY-ESO-1 specific TCR show activity with regression of synovial sarcoma and multiple myeloma.
9. Polyclonal T cell lines. Antigen-specific T cells (either CD4+ or CD8+) clones or polyclonal cell lines expanded ex vivo have been adoptively transferred to patients with cancer, typically melanoma. Response rates have been <20%, and poor T cell persistence has been the biggest obstacle to date.

 Current protocols for T cell therapies, particularly those described in Sections III.D.1.b to III.D.1.d, involve a conditioning regimen for the patient prior to adoptive T cell transfer. This conditioning consists of nonmyeloablative chemotherapy (i.e., cyclophosphamide ± fludarabine and in certain instances, total body irradiation with stem cell support) several days prior to the T cell infusion. The current thinking is that ablation of lymphocytes and myeloid cells results in increased availability of “space” and homeostatic cytokines (IL-7, IL-15) to support expansion of the infused T cells.

2. NK cell therapy. NK cells are large granular lymphocytes, phenotypically characterized as CD3 (TCR)- CD56+. NK cells exhibit natural cytotoxicity to tumors, and low cytotoxicity has been associated with increased cancer risk. NK cell recognition of tumors is complex and involves activating and inhibitory invariant receptors. Clinical studies using autologous and allogeneic NK cells have aimed to promote NK activity by modulating inhibitory and activating signals. The most promising disease indications for NK cell therapies are the hematological malignancies, especially in high-risk/relapsed AML after allogeneic transplantation. In this indication, adoptive transfer of allogeneic (mismatched inhibitory receptors) NK cells enhances cytotoxicity directed at tumors and the ability to control AML relapse.
3. Oncolytic viral therapies. These therapies are based on the use of viruses that either have tropism or can selectively replicate in tumors. Several viral platforms (herpes simplex type-1, vaccinia, and reovirus) are under development, and these viruses can be modified to promote tumor cell death, improve susceptibility to radiation and chemotherapy, or generate host antitumor immune responses. None of these therapies are FDA-approved at this time, and only those agents with the most promising clinical results are mentioned here.
4. Pexa-Vec (JX-594) consists of a vaccinia-virus backbone expressing GM-CSF and is designed to induce virus-replication–dependent tumor death as well as promote tumor immunity. The therapy has been delivered intratumorally and intravenously, and it is currently undergoing phase II trials in advanced hepatocellular carcinoma.
5. Talimogene laherparepvec (T-VEC) consists of a modified herpes simplex virus type-1 vector backbone expressing GM-CSF and is designed to induce virus-replication–dependent tumor death as well as elicit antitumor immunity. In a randomized phase III trial in melanoma, intratumoral delivery of T-VEC has shown a durable response rate of 16.3% versus 2.1% with the control GM-CSF.

 IV. IMMUNE-RELATED RESPONSE CRITERIA. Until recently, most oncology protocols required treatment discontinuation if there was any evidence of disease progression. During clinical development of ipilimumab, four distinct response patterns were noted: (a) shrinkage in baseline lesions without new lesions; (b) durable stable disease followed by a slow, steady decline in total tumor burden; (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions. Each pattern of response was associated with a prolonged survival. It was found that 9.7% of treated patients (n=227) with ipilimumab had disease progression at the week 12 assessments; however, at later time points they were found to have a radiographic response associated with patterns (c) and (d) (Clin Cancer Res 2009;15:7412). Given this type of “unconventional” responses observed, a new set of “Immune-related Response Criteria” incorporating the appearance of new measurable (and nonmeasurable) lesions with increased tumor burden has been proposed as more reliable response assessment criteria for use with immunotherapy clinical development programs. Investigators postulate that the apparent increased tumor burden reflects a brisk immune cell infiltration with edema into the tumor site as well as a transient increase in tumor volume prior to the development of a sufficient immune response that can lag temporally and take weeks to months after completion of ipilimumab treatment. For patients with modest disease progression and stable (ECOG 0-1) performance status after a course of ipilimumab, it is our practice to observe (no further therapy) and repeat imaging in 6 to 8 weeks to determine whether response pattern (c) or (d) is evident.

SUGGESTED READINGS

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