Transcript Immunotherapy

Immunotherapy: the good, the bad, the ugly
GAMC Meeting Jan 2017
Why immunotherapy?
Chrysoula I. Liakou, MD, PhD
Disclosures:
- Research Associate: Bristol-Myers Squibb
- Research Associate: Sanofi
Immunotherapy: The good
Die krankhaften Geschwülste. (The Morbid Tumors)
Virchow, Rudolph
Published by Hirschwald 1863-67, Berlin, 1863.
• In 1863 Virchow began publication of what was to be a comprehensive
review on the subject.
• It was never completed.
• Virchow stopped when he reached the point where carcinoma was to
be discussed, probably because of the vigorous attack he suffered from
the medical community.
• He described white blood cells in the tumor cells.
Immunotherapy: The good
Coley WB. The treatment of malignant tumors
by repeated inoculations of erysipelas: with a
report of ten original cases.
Am. J. Med. Sci. 1893; 105: 487-511.
• 1890s William Coley (1862–1936), a leading New York
surgeon, had a cancer patient (sarcoma) who had a complete remission following two attacks of erysipelas caused by acute
infection with the bacteria Streptococcus pyogenes.
• Coley injected streptococcal cultures provided by Robert Koch into cancer patients and observed tumour regression in
some cases. His findings were published in 1893, with his paper being the first that describes a serious attempt at cancer
immunotherapy.
• During the next 43 years Coley treated almost 900 cancer patients with his bacterial preparation which became known as
‘Coley’s toxin’. Most of the treated patients had inoperable sarcomas, with the bacterial toxin achieving a cure rate of over
10%.
• Despite these successes ‘Coley’s toxin’ was not widely accepted by the scientific and clinical communities of the time,
possibly due to the severe fever induced by the treatment and the perceived low cure rates.
• The general feeling amongst immunologists was that it would be impossible for the immune system to recognize and
respond to malignant cells. Woglom expressed this view in dramatic terms in a review in 1929 by stating that ‘It would
be as difficult to reject the right ear and leave the left ear intact as it is to immunize against cancer’!
(Woglom WH. Immunity to transplantable tumors. Cancer Res. 1929; 4: 129-38).
• Coley’s early studies led to the use of bacille Calmette-Guérin (BCG) for cancer immunotherapy, with this treatment being
used to the present day as the most effective therapy against superficial bladder cancer.
Cancer Immunotherapy – Yes or No?
A time line of the changing attitudes towards cancer immunotherapy.
1890s YES.
William Coley’s toxin induces tumor regression in some patients.
1900–50 NO.
NO
- Difficult to reproduce tumor regression with Coley’s toxin.
- Treatment highly toxic.
- No accepted theoretical framework for cancer immunotherapy.
1950s NO.
Sir Frank Macfarlane
Burnet, MD, PhD.
Virologist.
Nobel Prize 1960.
1960s YES.
Lloyd Old. MD.
TNF, BCG, p53
1970–85 NO – The viral era.
1949: Burnet proposes a model for cancer immunity but when they inject cancer cells in
animal models, “body recognizes cancer cells as “self”, therefore cannot reject them.
The Nobel Prize in Physiology or Medicine 1960 was awarded jointly to Sir Frank
Macfarlane Burnet and Peter Brian Medawar "for discovery of acquired immunological
tolerance“: Failure of immunological responsiveness, that is, inability of antigensensitive cells to synthesize antibodies; induced by
exposure to large amounts of an antigen. Immunological paralysis.
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Old LJ, Clarke DA, Benacerraf B. Effect of Bacillus Calmette Guerin infection on transplanted tumors in the mouse. Nature 1959
Jul 25; 184: 291-292. (PMID: 14428599)
•
Proposed that antitumor immune responses are directed against endogenous viruses
in tumors.
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Charlotte Friend characterizes a murine leukemia virus, later named the Friend leukemia virus (FLV). The Friend leukemia virus
is one of several discoveries leading to a resurgence in the virus theory of cancer in the 1960s and 1970s.
Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet 1964 Mar 28; 1:
702-703. (PMID: 14107961)
•
1995–2002 YES!!
Ralph Steinman,
MD, PhD.
Immunologist,
2011 – Nobel Prize
in Physiology or
Medicine.
James Alison, PhD.
Immunologist,
2015 – Lasker De
Bakey Award of
Medicine.
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2002 – 2017 The hipster era.
Dendritic cells can present tumor antigens to the adaptive immune system.
Many immunodeficient mice have much higher incidences of tumors
Emergence of the innate immune system as an important mediator of antitumor
immunity5
‘Stress’ induced markers can be recognized on tumor cells by the immune system
‘Immunosurveillance hypothesis’ resurrected but modified to incorporate the new
view that the immune system selects for tumors that can evade immune elimination
Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantification,
tissue distribution. J Exp Med 1973 May 1; 137: 1142-1162. (PMID: 4573839)
Allison JP, McIntyre BW, Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J
Immunol 1982 Nov; 129: 2293. (PMID: 6181166)
NIH has 816 million funding of immunotherapy research that comes down the pipeline.
Source: Cancer Research Institute.
The history of cancer immunotherapy:
from empirical approaches to rational, science-based therapies.
Immunotherapy was
declared the
Breakthrough of the
Year by Science
Imatinib approved
for CLL
Treatment
Treatment of
of bladder
cancer with
bacterial products cancer with
BCG
(“Coley’s toxin”)
1863 1898 1957 1976 1983 1991, 4
Description of
immune infiltrates Cancer
immunoin tumors by
surveillance
Virchow
hypothesis
(Burnet,
Thomas)
Source: Cancer Research Institute
Rituximab
approved for NHL
FDA approval of
sipuleucel-T
(DC vaccine) in
prostate cancer
Adoptive T
cell therapy
2001 2002
IL-2 therapy Discovery of
for cancer human tumor
antigens
2008
2003 2009
2010
HPV
vaccination
in VIN
-antiCD19 approved for NHL.
-Bortezomib approved for multiple
myeloma.
- Cefuximab – Erbitux approved
metastatic colorectal cancer.
- AVASTIN colorectal cancer.
FDA approval of
anti-PD1 for
melanoma
2013
2011
2014
2016
FDA approval of
anti-CTLA4
(ipilumimab) for
melanoma
1.
FDA approval
Pembrolizumab for
head and neck
cancer
2. Atezolizumab
antiIgG1 bladder
and lung cancer
3. First line tx of
melanoma and lung
cancer is
immunotherapy
The Carter story and the conspiracy theory
March 2016, USA Today.
Just months after finding out he had metastatic cancer, former President Jimmy Carter announced this weekend that his
doctors have said he no longer needs cancer treatment thanks in part to a groundbreaking new kind of medication that trains
the immune system to fight cancer tumors.
Carter announced in August that he had melanoma that had spread to his liver and brain. He underwent surgery, radiation
therapy and a new kind of cancer treatment called immunotherapy to fight the disease.
Speaking at his church this weekend, Carter announced that his doctors are stopping his immunotherapy treatment called
pembrolizumab after they saw no signs of tumors over a period of three months. While he has no evidence of the disease,
doctors will monitor Carter closely to see if the cancer reoccurs, a representative for the former president said.
"President Carter said today he did not need any more treatments, which he had August 2015 through February 2016, but will
continue scans and resume treatment if necessary,
Pardoll , Nature Immunol 2012.
Immune phenotypes that predict better survival
Analysis of 124
published articles on
correlation of T cell
subsets and prognosis
of 20 cancer types
Fridman et al. Nat Rev Cancer 12:298, 2012
Identification of tumor neoantigens
Ton N. Schumacher, and Robert D. Schreiber Science 2015;348:69-74
Immunotherapy: the bad
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Cytokine storm – T cells respond to target antigen:
– Requires anti-inflammatory therapy (anti-IL-6R).
– Risk of long-term damage (especially brain).
Unclear how well it will work against solid tumors:
– Problem of T cell entering tumor site.
Will tumors lose target antigen and develop resistance?
Technical and regulatory challenges of producing genetically modified CAR-T cells for each patient.
Prospect of gene-edited “universal” CAR-T cells?
One study found that fatigue was the most common side effect, along with fever, chills, nausea, and reactions
at the site of the infusion. Patients who receive these therapies need to be monitored for potentially more
serious adverse effects such as:
Pneumonitis (inflammation of the lungs resulting in cough and difficulty breathing).
Colitis (inflammation of the large bowel leading to diarrhea).
Hepatitis and pancreatitis.
Skin rashes.
Endocrine disorders including thyroid abnormalities and adrenal insufficiency.
Checkpoint blockade: Removing the brakes on the immune response
e.g. ipilimumab
Ribas A. N Engl J Med 2012;366:2517-2519.
Checkpoint blockade: Removing the brakes on the immune response
e.g. ipilimumab
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e.g. nivolumab, pembrolizumab
Ribas A. N Engl J Med 2012;366:2517-2519.
Bernardo SG, Moskalenko M, Pan M, et al. Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma. Melanoma Res 2013; 23:47.
Kim KW, Ramaiya NH, Krajewski KM, et al. Ipilimumab associated hepatitis: imaging and clinicopathologic findings. Invest New Drugs 2013; 31:1071.
Chmiel KD, Suan D, Liddle C, et al. Resolution of severe ipilimumab-induced hepatitis after antithymocyte globulin therapy. J Clin Oncol 2011; 29:e237.
Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol 2016.
Nishino M, Giobbie-Hurder A, Hatabu H, et al. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Metaanalysis. JAMA Oncol 2016; 2:1607.
Nishino M, Ramaiya NH, Awad MM, et al. PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course. Clin Cancer Res 2016; 22:6051.
Corsello SM, Barnabei A, Marchetti P, et al. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013; 98:1361.
Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal
cancer. J Immunother 2005; 28:593.
Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer
subtypes. Pituitary 2010; 13:29.
Hughes J, Vudattu N, Sznol M, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 2015; 38:e55.
Okamoto M, Okamoto M, Gotoh K, et al. Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig 2016; 7:915.
Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clin Gastroenterol Hepatol 2007; 5:70.
Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barré syndrome in a melanoma patient. Ann Oncol 2011; 22:991.
Maur M, Tomasello C, Frassoldati A, et al. Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J Clin Oncol 2012; 30:e76.
Bhatia S, Huber BR, Upton MP, Thompson JA. Inflammatory enteric neuropathy with severe constipation after ipilimumab treatment for melanoma: a case report. J Immunother 2009;
32:203.
Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro Oncol 2014; 16:589.
Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016; 375:1749.
Gordon IO, Wade T, Chin K, et al. Immune-mediated red cell aplasia after anti-CTLA-4 immunotherapy for metastatic melanoma. Cancer Immunol Immunother 2009; 58:1351.
Akhtari M, Waller EK, Jaye DL, et al. Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 antibody). J Immunother 2009; 32:322.
Delyon J, Mateus C, Lambert T. Hemophilia A induced by ipilimumab. N Engl J Med 2011; 365:1747.
Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother 2004;
27:478.
Immunotherapy: the ugly
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“Me-too” drugs.
Dr. Richard Pazdur, head of the Food and Drug Administration's office of oncology
products, was referring to therapies tumors use to evade the immune system.
The FDA has approved such treatments from Merck & Co, Bristol-Myers Squibb Co and
Roche Holding AG , each of which have list prices of $150,000 per year. At least five other
drug makers are developing similar medicines.
Pazdur acknowledged that the success of a few drugmakers in the worldwide $110
billion market for cancer treatments makes it attractive for rivals to continue
developing similar therapies rather than invest heavily in unproven approaches.
Merck and Roche are testing their PD-1s combined with chemotherapy for the same
purpose.
If combinations of expensive therapies become the norm, drugmakers could theoretically
keep prices lower by mixing their own treatments rather than seeking permission from a
rival.
New combination strategies for cancer therapy.
Checkpoint blockade: prospects and challenges
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Checkpoint blockade (anti-PD1/CTLA-4) + vaccination (DCs presenting tumor antigen).
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Checkpoint blockade + agonist antibody against activating receptor.
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Checkpoint blockade + kinase inhibitor to target oncogene.
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Exploiting combinations of checkpoints
– Poor biology underlying choice of combinations to block.
– Difficult to reliably produce agonistic antibodies.
Typically, 20-40% response rates; risk of developing resistance?
• Possible biomarkers of response vs resistance:
– Nature of cellular infiltrate around tumor.
– Frequency of tumor-reactive (“exhausted”) T cells.