Atlas of Response to Immunotherapy

123 Pages·2020·18.16 MB·English

by  Egesta Lopci, Stefano Fanti

Egesta Lopci
Stefano Fanti
Editors
Atlas of Response
to Immunotherapy
123
Atlas of Response to Immunotherapy
Egesta Lopci • Stefano Fanti
Editors
Atlas of Response to
Immunotherapy
Editors
Egesta Lopci Stefano Fanti
Nuclear Medicine Department of Metropolitan Nuclear Medicine
Humanitas Clinical and Research Policlinico S.Orsola-Malpighi
Hospital - IRCCS Bologna
Rozzano, Milano Italy
Italy
ISBN 978-3-030-31112-4 ISBN 978-3-030-31113-1 (eBook)
https://doi.org/10.1007/978-3-030-31113-1
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Preface
The armamentarium of publications on immunotherapy for oncological use has exponentially
increased in the last years. This is a direct consequence of the major impact of immunological-
based treatment on cancer and in particular of the wide adoption of checkpoint inhibitors: the
assignment of the 2018 Nobel Prize in Physiology or Medicine to the scientists who first
described the clinical utility of these new drugs confirms the relevance of the argument.
Consequently, there is a proliferation of texts on immunotherapy, and yet, why publish another
book on such a topic? When planning the outline of this book, our unique purpose was to
answer a clinical demand: how to investigate and interpret the tumor response to immuno-
therapy. In fact, much is known about principles and the role of immunotherapy, but much less
is clear about the best strategy to evaluate the response to therapy, in particular by imaging.
Being images the most immediate way to convey knowledge and taking into account our
expertise in molecular imaging, we could only choose an atlas as the best format to fit the
purpose, to clarify the issue and provide clear examples of clinical use.
Once we set up the aim of the project, the pathway to complete the task passed through the
involvement of great experts in the field. Despite the global attempt to assess the benefit of
immunotherapy in various oncological settings, the response evaluation by means of imaging
can still be considered unsettled. Anatomical imaging is based on morphology alone, there-
fore, it is not an optimal solution; on the other hand, functional imaging through metabolic
tracers can face problems of interpretation. An integrated approach taking advantage of both
information is probably the best way to procede, and thus we decided to focus on hybrid imag-
ing with PET/CT. A mindful and malleable way of thinking is nevertheless mandatory when
considering hybrid imaging for evaluating the response to therapy: not only clinicians must be
aware of the results obtainable on imaging, but most importantly they must know how to use
them. Imagers, on the other side, should acquire confidence in reading and documenting
results, allowing experience and proper knowledge transpire from the reports. Experience is in
fact a key element for every undertaking, even more crucial for medical specialty. This book
has focused on this specific element, providing by means of didactic images direct examples
of everyday experience with immunotherapy response assessment, not leaving aside excep-
tions and minority reports. We address the manuscript to every medical specialty involved in
the field and to trainees requiring insight on what to expect as specialists from molecular imag-
ing when tumor response to immunotherapy is questioned. Please enjoy the reading!
Milano, Italy Egesta Lopci
Bologna, Italy Stefano Fanti
v
Contents
Part I B rief Introduction
1 Immunotherapy in Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Paolo Andrea Zucali
2 Evolution of Response Criteria in Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . 7
Yan Liu
Part II Disease-Oriented Applications
3 CNS Tumors: PET/CT and MRI for Response Assessment
of CNS Tumors Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Egesta Lopci and Angelo Castello
4 Lung Cancer: 18F-FDG PET/CT for Response Assessment
of Lung Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Laura Evangelista and Giulia Pasello
5 Malignant Pleural Mesothelioma: 18F- FDG PET/CT
for Response Assessment of Malignant Pleural
Mesothelioma Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Egesta Lopci and Paolo Andrea Zucali
6 Melanoma: 18F-FDG PET/CT for Response Assessment
of Melanoma Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Christos Sachpekidis and Antonia Dimitrakopoulou-Strauss
7 Genitourinary Tumors: PET/CT for Response Assessment
of Genitourinary Tumors Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . 67
Egesta Lopci and Paolo Andrea Zucali
8 Hematologic Malignancies: PET/CT for Response Assessment
of Hematologic Malignancies Following Immunotherapy . . . . . . . . . . . . . . . . . . . 81
Angelo Castello and Egesta Lopci
9 Other Tumor Types: 18F-FDG PET/CT for Response Assessment
of Various Tumors Following Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Egesta Lopci and Angelo Castello
vii
viii Contents
Part III Potential Pitfalls to Response Assessment
10 Pitfalls and Immune-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Amir Iravani and Rodney J. Hicks
Part IV N ew Radiopharmaceuticals
11 ImmunoPET: The Future of Response Evaluation for Cancer
Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Emily B. Ehlerding and Weibo Cai
Part I
Brief Introduction
Immunotherapy in Oncology 1
Paolo Andrea Zucali
Introduction function) and tumor cells in the tumor microenvironment.
Targeting CTLA-4 or PD-1/PD-L1 reverses the exhaustion
The development of cancer immunotherapy is crucial in of cytotoxic T lymphocytes, thus leading to the elimination
the history of cancer therapy. In fact, the cancer immuno- of tumor cells via re-induction of the natural function of the
therapy demonstrated to be active showing durable T-cell population.
responses in several human cancers. Moreover, the safety Clinically, the anti-CTLA-4 antibodies (ipilimumab and
profiles of many cancer immunotherapy approaches tremelimumab), anti-PD-1 antibodies (nivolumab and pem-
resulted in milder and more manageable than traditional or brolizumab), and anti-PD-L1 antibodies (atezolizumab, ave-
targeted cancer therapy. lumab, and durvalumab) have produced remarkable results
Biologically, the loss of normal cellular regulatory pro- regarding tumor control in many malignancies (albeit in vari-
cess and the accumulation of several genetic alterations ous treatment lines), and they constitute a significant break-
characterized the cancer evolution determine the expression through in the treatment of cancer leading to improved
of neoantigens or differentiation antigens. These events can outcomes regarding progression-free (PFS) and/or overall
lead to the presentation of peptides bound to major histo- survival (OS) as compared to chemotherapy-based treatment
compatibility class I (MHCI) molecules on the surface of in patients who benefit from checkpoint inhibition.
cancer cells, discerning them from their normal counterpart.
The CD8+ T cells, produced spontaneously in cancer
patients, are able to recognize these cancer- specific peptide- Early Immunotherapeutics
MHCI complexes. Unfortunately, even when T-cell
responses occurred, they rarely induced protective immu- The first immunotherapy agent approved by the US Food and
nity, and the persistent deletion of cancer cells expressing Drug Administration (FDA) was an antitumor cytokine
T-cell targets (immune editing) may enable cancers to called interferon-alpha 2 (IFN-a2) in 1986. The IFN-a2 is
evolve to avoid attack [1, 2]. Overcoming negative regula- able to influence the immune system by both stimulating an
tors to T-cell responses in the tumor bed (immunostat func- innate cell-mediated response and creating an adaptive
tion) and in the lymphoid organs (checkpoints) could immune response and regulating cytokines and their recep-
explain the failure of immune protection in many patients. tors [4]. Initially, IFN-a2 was approved for the treatment of
In the tumor microenvironment, several factors, including hairy cell leukemia (HCL) due to the high response rate
PD-1/PD-L1, can work to modulate the existing activated observed in patients with progressive HCL [5, 6]. In 1995,
antitumor T-cell immune response, acting as an immune the use of IFN-a2 was approved also for the treatment of
rheostat or “immunostat” [3]. Therefore, the immune stage IIB/III melanoma.
response in cancer reflects a series of carefully regulated The second antitumor cytokine approved by the FDA in
events that may be perfectly well addressed not singly but as 1998 was interleukin-2 (IL-2), a T-cell growth factor that
a group. The immune checkpoint inhibitors modulate the aids in immune regulation and T-cell proliferation. In fact,
interaction between T cells (which are exhausted in their IL-2 demonstrated to be able to significantly improve sur-
vival of patients with metastatic melanoma and renal cell
carcinoma [6].
P. A. Zucali (*) The use of intravesicular bacillus Calmette-Guerin (BCG)
Department of Medical Oncology, Humanitas Clinical
was approved by FDA in 1990 for noninvasive, stage Tis, Ta,
and Research Hospital—IRCCS, Rozzano, Milano, Italy
e-mail: [email protected] and T1 bladder cancers. The BCG, after its internalization by
© Springer Nature Switzerland AG 2020 3
E. Lopci, S. Fanti (eds.), Atlas of Response to Immunotherapy, https://doi.org/10.1007/978-3-030-31113-1_1
4 P. A. Zucali
urothelial and tumor cells, is presented to the immune s ystem ligand is confined within tumors, and not in noninflamed
via antigen-presenting cells (APCs), causing the bladder normal tissues, targeting this checkpoint pathway focuses
cells to release cytokines and recruit immune cells to attack the biological effects and translates to much lower rates of
any cells containing BCG [7]. Since BCG is also internalized toxic effects than for anti-CTLA-4. The anti-PD-1 drug
by tumor cells, the immune system is able to recognize the nivolumab showed durable tumor regressions in a substan-
cells and subsequently attack them [7]. tial proportion of otherwise refractory melanomas, kidney
cancers, and lung cancers in a small first-in-human trial
[10]. The finding that lung cancer (previously considered to
Immune Checkpoint Inhibitors be nonimmunogenic) proved responsive to anti-PD-1
induced the launch of clinical trials of multiple anti-PD-1
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) was the first and anti-PD-L1 drugs in many types of cancer. In 2014, two
immune checkpoint receptor discovered and characterized. PD-1 inhibitors (pembrolizumab and nivolumab) were
Antibodies blocking CTLA-4 demonstrated to be able to approved by FDA for use in metastatic melanoma
mediate the regression of established tumors in animal mod- (Table 1.1). Since 2014, the FDA has expanded the use of
els, leading to clinical test in patients with cancer [8]. In pembrolizumab and nivolumab for multiple different sites
2011, ipilimumab was approved by FDA for advanced mela- that include non-small-cell lung carcinoma, Hodgkin lym-
noma based on long-term OS in approximately 20% of phoma, Merkel cell carcinoma, kidney and bladder cancer,
patients (Table 1.1). The high rate of immune-based toxic head and neck cancer, and tumors with a genetic marker of
effects (rash, colitis, thyroiditis, and hepatitis among others) high mutational burden termed microsatellite instability
represented a major limitation of CTLA-4 blockade [9]. (MSI) (Table 1.1). In 2016, FDA approved the first PD-L1
The pathway comprising PD-1, an inhibitory receptor inhibitor, atezolizumab, for use in metastatic urothelial car-
expressed on activated tumor-specific CD4+ helper and cinoma [11–17]. The proportions of patients responding to
CD8+ killer T lymphocytes, and its major ligand PD-L1 PD-1/PD-L1 inhibitors are variable depending on cancer
was the next checkpoint target to enter clinical testing. If type and treatment setting (first-line versus later- line ther-
the CTLA-4 checkpoint modulates early activation of sys- apy), ranging approximately from 15 to 65%. The generally
temic T-lymphocyte immunity, PD-1 modulates the activity favorable safety profile of anti-PD-1/PD-L1 therapies and
of trained killer T lymphocytes that have migrated into their ease of administration have supported adoption of
tumors. Considering that the overexpression of the PD-L1 anti-PD-1 therapies in community oncology practices.
Table 1.1 Approved uses of CTLA-4, PD-1, and PD-L1 inhibitors
Agent Mechanism of action Approved disease sitesa
Ipilimumab CTLA-4 inhibitor • Adjuvant therapy for stage 3 melanoma
• Metastatic melanoma
Nivolumab PD-1 inhibitor • Metastatic melanoma
• Metastatic non-small-cell lung cancer
• Metastatic renal cell carcinoma
• Classical Hodgkin lymphoma
• Recurrent or metastatic squamous cell carcinoma of the head and neck
• Mismatch repair deficient or microsatellite instability-high colorectal cancer
• Hepatocellular carcinoma
• Locally advanced or metastatic urothelial carcinoma
Pembrolizumab PD-1 inhibitor • Metastatic melanoma (first line)
• Metastatic non-small-cell lung cancer (PD-L1 expression–dependent)
• Recurrent or metastatic squamous cell carcinoma of the head and neck
• Classical Hodgkin lymphoma
• Microsatellite instability-high cancers
• Recurrent locally advanced or metastatic gastric or gastroesophageal junction
adenocarcinoma (PD-L1 expression–dependent)
• Locally advanced or metastatic urothelial carcinoma
Nivolumab + ipilimumab PD-1 + CTLA-4 inhibitors • Metastatic or unresectable melanoma (first line)
Atezolizumab PD-L1 inhibitor • Locally advanced or metastatic urothelial carcinoma
• Metastatic non-small-cell lung cancer
Durvalumab PD-L1 inhibitor • Locally advanced or metastatic urothelial carcinoma
Note: CTLA-4 cytotoxic T-lymphocyte-associated antigen 4, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1
aApproval in the second-line metastatic setting unless otherwise noted