A Brief History of Immunotherapy

Early Work

William B. Coley, MD, now known as the Father of Immunotherapy, first attempted to harness the immune system for treating cancer in the late 19th century. Having noted a number of cases in which patients with cancer went into spontaneous remission after developing erysipelas, he began injecting mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens into patients’ tumors in 1891.

Coley achieved responses such as durable complete remission in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. The lack of a known mechanism of action for ‘Coley’s toxins’ and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments early in the 20th century.¹

The strategy of using attenuated bacteria to treat malignancies resurfaced in 1976 when a trial was conducted to test the use of the tuberculosis vaccine Bacille Calmette-Guérin (BCG) as a means of preventing the recurrence of nonmuscle invasive bladder cancer.²BCG therapy was very effective and continues to be used today.

James P. Allison, PhD, Discusses Future Immune Checkpoint Strategies

Allison is the director of the immunotherapy platform at The University of Texas MD Anderson Cancer Center.

IL-2

Antibody Therapies

Vaccines

The idea of using immunotherapy in cancer, in general, returned to prominence when Thomas and Burnet first proposed the theory of cancer immunosurveillance in 1957. They suggested that lymphocytes acted as sentinels to identify and eliminate somatic cells transformed by spontaneous mutations.³The absence of data supporting the existence of tumor-specific antigens and the technical inability to culture and manipulate lymphocytes in vitro postponed further progress in this area for some time.The T-cell growth factor interleukin 2 (IL-2) was identified in 1976,⁴allowing investigators to culture T cells in vitro for the first time. Large doses of IL-2 were shown to be effective when administered to patients with established, metastatic cancers by enhancing T-cell production.⁵The use of IL-2 as an immunotherapeutic agent eventually gained US Food and Drug Administration (FDA) approval in metastatic kidney cancer in 1991, and in metastatic melanoma in 1998.In the 1970s, Milstein and Köhler pioneered the production of monoclonal antibodies in the laboratory using hybridomas, antibody-secreting cell lines formed by the fusion of lymphocytes with myeloma cell lines.⁶Research on antibody-based therapies eventually led to the development of rituximab, which binds to CD20 on the surface of immature B cells and targets them for elimination by natural killer cells.⁷The first monoclonal antibody approved by the FDA for the treatment of a cancer, non-Hodgkin’s lymphoma, came in 1997.In 1991, researchers cloned a melanoma-derived antigen that could induce a response from cytotoxic T cells.⁸In 2007, Olivera J. Finn, PhD, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania described this paper as “the molecular divide between the ‘old’ human tumor immunology that postulated but could not prove the existence of tumor antigens (Ags) and the ‘new’ tumor immunology that uses these Ags and genes that encode them to understand tumor immunity and design effective immunotherapy.”⁹

Current Trends

Clinically effective vaccines remained elusive, however, until 2010, when the FDA approved the first cancer vaccine, sipuleucel-T, for castration-resistant prostate cancer. This dendritic cell vaccine was able to extend overall survival of patients in clinical trials, although it did not have any effect on the time to disease progression.¹⁰There are several emerging trends in immuno-oncology, including checkpoint inhibitors and adoptive T-cell therapy (ACT). Immune checkpoint components—such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) and its ligand (PD-L1)—are expressed on tumor-infiltrating lymphocytes and many types of tumor cells, and they allow malignant cells to evade cytotoxic immune responses. Ipilimumab, an antibody targeting CTLA-4 approved by the FDA for use in patients with melanoma, inhibits this process and facilitates T-cell activation against tumor cells. Antibodies targeting PD-1 and PD-L1 are also being tested in phase III trials against several types of tumors. This year in Japan nivolumab became the first PD-1 inhibitor to achieve regulatory approval in melanoma. Promising results have also been posted for the experimental anti-PD-L1 antibody MPDL3280A in melanoma, lung cancer, and bladder cancer.^11,12

Clinical Pearls

• William B. Coley, MD injected live and inactivated Streptococcus pyogenes and Serratia marcescens into patients’ tumors in 1891 to try to harness the immune system in the treatment of cancer.
• Lack of a known MOA for ‘Coley’s toxins’ and the risks of infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as standard treatments.
• In the 1970s, large doses of IL-2 were shown to be effective when administered to patients with established, metastatic cancers by enhancing T-cell production.
• The first monoclonal antibody approved by the FDA for the treatment of a cancer, non-Hodgkin’s lymphoma, came in 1997.
• In 2010, the FDA approved the first cancer vaccine, sipuleucel-T, for castration-resistant prostate cancer.
• In 2011, Ipilimumab, an antibody targeting CTLA-4 was approved by the FDA for use in patients with melanoma.
• In 2014, in Japan nivolumab became the first PD-1 inhibitor to achieve regulatory approval in melanoma.
• Promising results have also been posted for the experimental anti-PD-L1 antibody MPDL3280A in melanoma, lung cancer, and bladder cancer.^11,12

In ACT, T cells activated against tumor-specific antigens are isolated from the patient, expanded ex vivo, and then reintroduced into the patient. A phase I study presented at the 2014 ASCO Annual Meeting tested human papillomavirus (HPV)-specific T cells in patients with metastatic cervical cancer and produced several durable complete responses.¹³

“Clearly, the ability to manipulate components of the immune system with drugs and to manipulate and activate an individual patient’s cells in the laboratory are the areas with great interest and activity now,” said Clifford A. Hudis, MD, the chief of breast cancer medicine service at Memorial Sloan Kettering Cancer Center in New York City, although he warned that clinicians should avoid creating unreasonable expectations among patients.

“The key point physicians have to convey to lay audiences is the power of the immune system and the fact that manipulating it can cause significant toxicities that require expert management. It is not as simple as stimulating the immune system,’ a misleading phrase that many patients find attractive,” Hudis stated.

References

1. Decker WK, Safdar A. Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley’s legacy revisited.Cytokine Growth Factor Rev. 2009;20(4):271-281.
2. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors.J Urol. 1976;116(2):180-183.
3. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape.Nat Immunol. 2002;3(11):991-998.
4. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows.Science. 1976;193(4257):1007-1008.
5. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.N Engl J Med. 1985;313(23):1485-1492.
6. Milstein C. The hybridoma revolution: an offshoot of basic research.Bioessays. 1999;21(11):966-973.
7. Rudnicka D, Oszmiana A, Finch DK, et al. Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity.Blood. 2013;121(23):4694-4702.
8. van der Bruggen P, Traversari C, Chomez P, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.Science. 1991;254(5038):1643-1647.
9. Finn OJ. Human tumor immunology at the molecular divide.J Immunol. 2007;178(5):2615-2616.
10. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.N Engl J Med. 2010;363(5):411-422.
11. Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.J Clin Oncol. 2013;31 (suppl): Abstract 3000.
12. Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC).J Clin Oncol. 2014;32 (suppl): Abstract 5011.
13. Hinrichs CS, Stevanovic S, Draper L et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.J Clin Oncol. 2014;32 (suppl): Abstract LBA3008.