Harnessing the immune system to cure cancer

Despite the major advances in diagnosis and multimodal therapy, cancer remains the leading cause of death in the world. Most of cancer death is due to the spread of malignant cells to vital organs, such as the lung, the liver and the brain. Chemotherapy is usually the standard of treatment for metastatic cancer patients. The overall survival (OS) benefit is modest. The systemic side toxicity and drug resistance further limit their long-term application. “The War on Cancer” hasn’t been very promising during the last several decades. The latest breakthrough in cancer care is the approval of anti-tumor immunotherapeutic drugs-ipilimumab for metastatic melanoma in 2011. The curative potential of cancer immunotherapies is beginning to be realized. For examples, the woman with lung metastasis from melanoma has been alive and healthy for 13 years; the 6-year-old child near death from leukemia is now in third grade and the cancer remains in remission (1). Therefore, Science magazine ranked cancer immunotherapy as the “scientific breakthrough of 2013”. In line with this progression, the theme for the 2014 American Association for Cancer Research (AACR) annual meeting was “Harnessing Breakthroughs-Targeting Cures”. This is the first time ever that AACR talked about curing cancers.

Cancer is considered as a genetic disease. Recent progress in caner genome sequencing showed that different cancers carry a variable number of genetic alterations. Melanoma and lung tumors harbor many more mutations than average, which contain about 200 nonsynonymous mutations per tumor (2). Those mutations, theoretically, can be recognized as neoantigens or differentiation antigens by immune cells, which constantly patrol tissues to identify and destroy foreign invaders and abnormal cells. However, the development of clinically manifest tumors indicates that tumors are able to escape the host immune surveillance. Dr. Schreiber and his colleagues postulated a process named as “Cancer Immunoediting” to describe the dynamic interactions between immune system and tumors. Cancer immunoediting occurs in three sequential phases: elimination, equilibrium, and escape (3,4). Therefore, cancer immunotherapy is usually designed to overcome the escaped mechanisms of cancers and to resuscitate immune effector cells to eradicate malignant cells.

Strategies to induce anticancer immune response can be broadly divided into two categories: non-antigen-specific and antigen-specific. Non-antigen-specific approaches include immune checkpoint blockers and non-specific immune cell activation, whereas antigen-specific approaches include a variety of cancer vaccines, adoptive transfer of autologous cancer-specific T cells or genetic engineered T cells. Examples of anticancer therapeutics in both categories have recently received regulatory approval, and many other agents are being evaluated in randomized phase II or III clinical trials.

Immune checkpoint blockers

Immune checkpoints are a group of T cell co-inhibitory molecules, which regulate the duration and amplitude of the immune response of T cells. Thus, under normal physiological conditions, immune checkpoints are crucial for the maintenance of self-tolerance and to protect tissues from damage during pathogenic infection. It is now clear that tumors co-opt certain immune checkpoint pathways as a major mechanism of immune resistance. A growing body of evidences suggest that unleashing the brake on immunity can elicit T-cell mediated anticancer immune response and provide therapeutic benefits in advanced cancer treatments. Dr. Allison and his colleagues found that cytotoxic T-lymphocyte antigen 4 (CTLA4) acts as a negative regulator to suppress T cell activation and proposed that blockade of CTLA4 can restore anti-cancer T cell immunity (5). In a landmark phase III clinical trial in patients with previously treated metastatic melanoma, ipilimumab, a monoclonal antibody that blocks CTLA4, significantly prolonged OS compared to gp100 vaccination therapy alone (median OS in gp100, ipilimumab, ipilimumab plus gp100 cohorts are 6.4, 10.0, 10.1 months, respectively) (6). More importantly, the long-term follow-up analysis showed that five-year OS ranges from 13.8% to 49.5% in a variety of clinical trials with different doses of ipilimumab treatment (7). This is a milestone in advanced melanoma cancer patient treatment.

Another immune checkpoint that has attracted lots of attention is the PD1/PD-L1 signaling pathway. PD-1 is often expressed on activated T cells that dampens the T cell immune response. PD-1’s endogenous ligands, PD-L1 and PD-L2, are expressed in a number of cell types, including tumor cells (8). Blockade of PD-1 or PD-L1 has achieved impressive clinical benefit in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and melanoma in several initial clinical trials (9-11). PD1/PD-L1 blockers seem to possess milder side effect profile than anti-CTLA4 antibody treatment. Furthermore, PD-1 has distinct immune regulatory mechanism and acts in a different stage of T cell activation, compared to CTLA4. These properties suggest that the blockade of both simultaneously might offer better anti-tumor activity. Besides CTLA4 and PD1/PD-L1, several other immune regulatory molecules have been identified and their therapeutic potentials are being tested in both pre-clinic and clinic settings (12).

Contingent to the physiological roles of immune checkpoints, blockade of immune checkpoints generated immune-related adverse events, such as fatigue, fever, chills, rash, diarrhea, colitis and pneumonitis (6,7,9,10). Although early applications of immune checkpoint blockers caused a small portion of patient deaths, life-threatening complications have been minimized by using mechanism-based algorithms (7). For example, the administration of systemic corticosteroids can effectively and rapidly reverse the symptoms of colitis in the majority of patients (6,7). Therefore, the safety profiles of cancer immunotherapies are often milder and more manageable, compared to traditional or targeted cancer therapies.

Adoptive cell transfer and chimeric antigen receptor (CAR) T cells

Adoptive T cell therapy (ACT) involves the isolation and reinfusion of in vitro expanded and activated tumor-antigen specific T cells into patients, aiming to eliminate malignant cells (13). Dr. Rosenberg and his colleagues pioneered the application of autologous ACT for treatment of patients with advanced melanoma (13). ACT immunotherapies were reported to achieve 20-50% cure rates in metastatic melanoma (14,15). The high curative potential of ACT in melanoma has inspired the attempts to explore this regimen in other cancer types, unfortunately the efficacy hasn’t been very promising. Cancer genomic data suggested that melanoma harbors higher mutation rates than other cancers, which may explain, at least in part, why melanoma often responses well to cancer immunotherapies, including ACT and immune checkpoint blockers, but not other epithelial cancers (2,15). The limitations of conventional ACT include the low affinity to tumor-specific antigens, central tolerance and the potent immunosuppressive microenvironment. Subsequently, genetically engineered T cells, such as CAR T cells, were developed, aiming to overcome those shortcomings (16). A distinct CAR T cells contain three modules: an extracellular target binding domain derived from an antibody fragment, a transmembrane module and an intracellular signal module providing costimulatory signals (16). CARs have shown spectacular outcomes in several hematological malignancies, such as B cell malignancies, and are now being evaluated for solid tumors. These approaches also face many disadvantages, including the availability of specific tumor antigens, the persistence of infused T cells, the trafficking of effector cells into tumor sites, and the negative regulators to T cell activity in the tumor bed.

Cancer vaccines

Vaccines represent a traditional approach with enormous medical success, especially in the prevention of infection diseases. Therapeutic cancer vaccines are designed to activate and boost the body’s immune cells to attack growing malignant cells (17). Numerous approaches have been developed to stimulate anti-cancer immunity, including dendritic cells, whole tumor cells, proteins, peptides, viral vectors, bacteria, nucleic acids (DNA and RNA), and a variety of adjuvant. US FDA approved the first therapeutic cancer vaccine sipuleucel-T for advanced prostate cancer in 2010 (18). However, the clinical benefits of cancer vaccine therapy remain modest and are usually difficult to predict (15). A recent advance in cancer vaccination is to employ tumor cells as a type of endogenous vaccine under cytotoxic therapies. Chemotherapy, radiotherapy, and targeted therapy are able to cause cancer cell death in a fashion to induce anti-cancer immune responses, but achieving it requires specific chemotherapeutic agents and appropriate doses (19).

Targeting tumor-associated macrophages (TAMs)

TAMs are one of the major cellular components within the tumor microenvironment. However, instead of acting as immune defenders that fights cancer, macrophages are often hijacked by cancers to suppress host immune responses and facilitate tumor progression. Within solid tumors, TAMs typically compose of a heterogeneous cell population that has M1, M2 and intermediate phenotypes (20). M1-like TAMs have anti-tumor activity, while M2-like TAMs promote tumor progression and metastasis. The tumor microenvironment consists of various immune inhibitory cytokines and growth factors that polarize TAMs to pro-tumoral and immunosuppressive M2-like phenotype (20,21). Therefore, converting TAMs to their natural immune surveillance status provides a powerful approach to promote immune mediate anti-cancer response and inhibit tumor growth. Targeting CSF-1R signaling or reduce tumor tissue hypoxia has been shown to alter TAM phenotypes and suppress tumor progression (22,23).

Combinational therapy

Although durable monotherapy responses are being constantly reported for several different immunotherapeutic agents in a broad range of metastatic human cancers, the response rates are still low. Curing cancer is an extremely challenging task. Tumors are highly heterogeneous, including interpatients, intertumors, intratumor and intercellular heterogeneity (24). This cellular and molecular heterogeneity is difficult to overcome with single target. Furthermore, cancer has developed multiple mechanisms to escape host immune surveillance, such as immune checkpoints, central tolerance, and the immunosuppressive tumor microenvironment. Therefore, multimodal immunotherapy as well as combinational therapy to simultaneously overcome intrinsic and extrinsic tumor immune tolerance seems to be necessary to achieve optimal clinical benefits. The combination of anti-CTLA4 and anti-PD-1 increase the response rate and improve anti-cancer efficacy, compared to monotherapies (25). The combination of vaccine therapy and immune checkpoint blockers showed better tumor growth inhibition. Many different combinational cancer immunotherapies are being tested in various cancer models (26,27).

Concluding remarks

Active cancer immunotherapy is in the limelight of cancer treatments. Its long-term survival benefit with curative potential is attracting more and more attentions from oncologists, patients, cancer researchers and pharmaceutical companies. However, the overall response rate remains low. To fully realize the potential of cancer immunotherapies in the future will rely on the new insight into the key immune tolerant mechanisms, the identification of reliable immune biomarkers to stratify cancer patients and perform personalized immunotherapy, and the development of more effective and safer combinational regimens to maximize anticancer efficacy.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.3978/j.issn.2218-676X.2014.06.08). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013;342:1432-3. [PubMed]
2. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. Science 2013;339:1546-58. [PubMed]
3. Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012;482:400-4. [PubMed]
4. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565-70. [PubMed]
5. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002;3:611-8. [PubMed]
6. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. [PubMed]
7. Page DB, Postow MA, Callahan MK, et al. Immune modulation in cancer with antibodies. Annu Rev Med 2014;65:185-202. [PubMed]
8. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol 2013;94:25-39. [PubMed]
9. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369:134-44. [PubMed]
10. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. [PubMed]
11. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64. [PubMed]
12. Garber K. Beyond ipilimumab: new approaches target the immunological synapse. J Natl Cancer Inst 2011;103:1079-82. [PubMed]
13. Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299-308. [PubMed]
14. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550-7. [PubMed]
15. Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med 2012;4:127ps8.
16. Barrett DM, Singh N, Porter DL, et al. Chimeric antigen receptor therapy for cancer. Annu Rev Med 2014;65:333-47. [PubMed]
17. Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity 2013;39:38-48. [PubMed]
18. Madan RA, Gulley JL, Fojo T, et al. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist 2010;15:969-75. [PubMed]
19. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31:51-72. [PubMed]
20. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012;122:787-95. [PubMed]
21. Huang Y, Snuderl M, Jain RK. Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. Cancer Cell 2011;19:1-2. [PubMed]
22. Pyonteck SM, Akkari L, Schuhmacher AJ, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 2013;19:1264-72. [PubMed]
23. Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 2012;109:17561-6. [PubMed]
24. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013;501:328-37. [PubMed]
25. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33. [PubMed]
26. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 2012;12:237-51. [PubMed]
27. Huang Y, Goel S, Duda DG, et al. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013;73:2943-8. [PubMed]