IMMUNOTHERAPY

Cancer Immunotherapy

Recent advances in tumor immunology are paving the way for an enhanced understanding of the interactions between cancer and the immune system and strategies to re-activate immune responses and reverse the fundamental mechanisms cancer cells utilize to elude detection and destruction by the immune system.1,2 Recent  evidence shows the introduction of cancer immunotherapies has resulted in improved patient outcomes in several cancer types.2 Immunotherapy strategies includes monoclonal antibodies, cell or antigen based vaccines, and small molecules targeting immune cells processes.  Cancer cells hijack and elude the body’s immune system impacting its ability to suppress tumor cell growth via several mechanisms (table1).3,4 Innate immunity is non-specific and plays a minimal role in the immunotherapy discussion though, adaptive immunity plays a critical role in the antitumor processes stemming from its ability to differentiate “self” from “non-self” with immunomemory.3

Compared to chemotherapy and targeted agents, immune checkpoints inhibitors have shown unique modalities of responses (e.g. pseudoprogression) that require specific changes in monitoring and assessment of their efficacy.  With the introduction of techniques such as the Immune-related Response Criteria (irRC) in 2009 by the Cancer Immunotherapy Consortium (CIC), the RECIST criteria and other clinical efficacy outcome measure techniques, activity patterns changes are able to be evaluated and reported in large trials with careful attention to clinical outcome details specific to immunotherapy, though further research is needed to enhance and standardize these methodologies 5,6. Additionally, more data and evaluation is necessary to monitor and control immune related adverse events (irAEs), which are unique to immune checkpoint inhibition and are due to essentially ‘inducing autoimmunity’.7,8

 

 

 

 

Table 1

Immune Checkpoint Inhibitors

FDA approved checkpoint inhibitors include anti-PD-1, anti-PD-L1, and anti-CTLA4 monoclonal antibodies.

  • T-cell activation requires a series of interactions between receptors on the T-cell and those on antigen presenting cells (APCs). An important part of T-cell activation are the regulatory signals needed to prevent autoimmunity.10 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) receptor are checkpoints needed to prevent unnecessary T-cell activation and were the first useful targets for immunotherapy.10,11 CTLA-4 are expressed by naïve T-effector cells and T-regulatory cells. Stimulation of naïve T-cells results in an upregulated expression of CTLA-4 that competes with CD-28 (needed for co-induction) thus suppressing T-cell activity.7,8,12 When PD-1 binds to one its ligands (PD-L1 or PD-L2), the activity of T-cells is suppressed allowing cancer cells to evade detection by the immune system.3,10,12
  • Specific biomarker for anti-PD-1 and PD-L1 inhibitors to predict individual response are under investigation, though intervariable patterns of expression among patients and during disease progression still needs further evaluation.12

Table 2

Immune Related Adverse Events (irAE):

Immune related adverse events (irAE) result from the activation and proliferation of T-cells and proinflammatory reactions stemming from the use of Immune checkpoint inhbitors (Fig.1). 15,16 Though more data is needed to solidify a standard for treating irAEs, the oncology field is actively providing individual cases and small studies to better understand the exact mechanisms that give rise to irAE’s with the goal of optimizing their management and patient outcomes. An important part of managing these irAE’s is the understanding that they can occur at any time during treatment and any signs and symptoms should be carefully evaluated, treated and monitored.

  • Thyroid disorders caused by immunotherapy include thyrotoxicosis leading to hypothyroidism, hyperthyroidism, euthyroidism, Graves hypothyroidism and very rarely, thyroid storm.15,17 Hypothyroidism can require permanent thyroid replacement treatment in patients who received anti-PD-1 therapy alone or in combination with anti-CTLA-4 therapy.15
  • Hypophysitis (inflammation of the pituitary gland) that usually occurs 8-9 weeks after initiation of treatment.15 Fatigue, headache, weakness, memory loss, impotence, mood changes and visual field impairment are some of the early nonspecific signs and symptoms.17 The standard of therapy for treating hypophysitis is hormone replacement.17   Anti-CTLA-4 related hypophysitis mainly leads to disruption in secretions of the anterior pituitary gland (i.e. ACTH, TSH, LH, FSH, GH, prolactin), though, evidence shows deficiencies in ACTH and TSH are most common in this patient cohort.15 Close monitoring of adrenal and thyroid functions is essential for any patient starting anti-CTLA-4 therapy.15 Hyponatremia is another possible sign of anti-CTLA related hypophysitis, and is usually resolved with adrenal and thyroid hormone treatment.15 Treatment for anti-CLTA-4 related hypophysitis includes hormone placement with glucocorticoids, thyroid hormone, testosterone or estrogen unless contraindicated.15
  • Cutaneous irAE’s include rash and vitiligo.18 Skin rashes restricted to small areas on the skin may be treated with topical corticosteroids, while more serious skin rashes can be treated with topical, oral or IV steroid.17 Anti-PD-1 therapy has been associated with these cutaneous irAEs (and specifically maculopapular rash), along with alopecia.17,18 Vitiligo has been reported with use of CTLA-4 inhibitors and anti-PD-1 treatment though, in patients with melanoma vitiligo is associated with improved OS.18
  • Sarcoidosis and other pulmonary toxicities have been associated with PD-1 blockade and anti-CLTA-4 therapy, though a recent case report provides supportive evidence of the heavy influence of PD-1 blockade on the development of sarcoidosis.17,19 Any new onset on respiratory symptoms (i.e. cough or shortness of breath that was not present before) should be carefully evaluated and systemic corticosteroids may be used if treatment is warrented.17
  • GI irAEs include mucositis and diarrhea (severe in some cases).17,18 Treatment for diarrhea depends on severity- low grade diarrhea can be treated with antidiarrheal therapy and supportive therapy as needed. Corticosteroids may be added to treatment for persistent or refractory diarrhea.17
  • Hepatotoxicity is a rare irAE. Symptoms include fever, increased transaminases and/or increased bilirubin.17 Monitoring liver function prior to and during treatment is advisable. Treatment for hepatotoxicity includes discontinuation of treatment until improvement and IV corticosteroids.17

Fig.3 (courtesy Dr. Balar A.)

References:

  1. Dunn J, Rao S. Epigenetics and immunotherapy: The current state of play. Molecular Immunology. 87. Pp 227-239
  2. Freema-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clinical Cancer Research. 2015. 22(4). Doi: 10.1158/1078-0432.CCR-15-1136
  3. De Felice F, Marchetti C, Palaia I, Musio D, et al. Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. Journal of Immunology Research. Article ID 191832. http://dx.doi.org/10.1155/2015/191832
  4. Peterson JJ, Steele-Moses SK. Update on New Therapies With Immune Checkpoint Inhibitors. Clinical Journal of Oncology Nursing. Vol 20, No 4.
  5. Hoos A, Wolchok JD, Humphrey RW, Hodi FS. CCR 20th Anniversary Commentary: Immune-Related Response Criteria- Capturing Clinical Activity in Immune Oncology. Clin Cancer Res (2015); 21(22)
  6. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 2009. 45. 228-247
  7. Kong YK, Flynn JC. Opportunistic autoimmune disorders potentiated by immune-checkpoint inhibitors anti-CTLA-4 and anti-PD-1. Frontiers in Immunology. Vol 5, Article 206. Doi: 10.3389/fimmu.2014.00206
  8. Spigel DR, Socinski MA. Rationale for Chemotherapy, Immunotherapy, and Checkpoint Blockade in SCLC: Beyond Traditional Treatment Approaches. J Thorac Oncol. 2013;8(5): 587-598.
  9. De Felice F, Marchetti C, Palaia I, Musio D, et al. Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors. Journal of Immunology Research. Article ID 191832.
  10. Gelao L, Criscitiello C, Esposito A, et al. Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander”. 2014, 6, 914-933. Doi:10.3390/toxins6030914
  11. Kong YK, Flynn JC. Opportunistic autoimmune disorders potentiated by immune-checkpoint inhibitors anti-CTLA-4 and anti-PD-1. Frontiers in Immunology. Vol 5, Article 206. Doi: 10.3389/fimmu.2014.00206
  12. Dunn J, Rao S. Epigenetics and immunotherapy: The current state of play. Molecular Immunology. 87. Pp 227-239
  13. Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treatment Reviews. 2017(54) 28-67
  14. Callahan MK, Rostow MA, Wolchol JD. Targeting T Cell Co-receptors for Cancer Therapy. Immunity Review. 2016, 44
  15. Min L. Immune-related endocrine disorders in novel immune checkpoint inhibition therapy. Genes & Diseases. 2016. 3, 252-256. http://dx.doi.ord/10.1016/j.gendrs.2016.10.002
  16. Berman D, Korman A, Peck R, Feltquate D, Lonberg N, Canetta R. The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: The Bristol-Myers Squibb experience. Pharmacology & Therapeutics. 148 : 132-153
  17. Fay AP, Moreira B, Nunes Filho PRS, Albuquerque C, Barrios CH. The management of immune-related adverse events associated with immune checkpoint blockade. Expert Review of Quality of Life in Cancer Care. Vol 1. No 1, pp 89-97. http://dx.doi.org/10.1080/23809000.1142827
  18. Freema-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes. Clinical Cancer Research. 2015. 22(4). Doi: 10.1158/1078-0432.CCR-15-1136
  19. Birnnaum MR, Ma MW, Fleisig S, et al. Nivolumab-related cutaneous sarcoidosis in a patient with ling adenocarcinoma. JAAD Case Reports. 2017;3:208-11. http://dx.doi.org/10/1016/j.jdcr.2017.02.015