Page 1080 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 77 Immunotherapy of Cancer 1045

Recent findings from a retrospective study involving two clinical
trials with ipilimumab in patients with prostate cancer identified Biomarkers
CD8 T-cell clonal expansion within the systemic circulation as To identify potential biomarkers that are relevant to antitumor
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a potential correlative biomarker of irAEs. These findings immune responses, clinical trials are being designed to obtain
highlight a potential biomarker to predict, and provide early tumor tissues to gain a better understanding of the tumor
intervention for, toxicities that occur in patients who receive microenvironment and of immunological changes that occur
10
ipilimumab therapy. over time. Several biomarkers have been associated with clinical
outcomes to immune checkpoint therapy, including high levels
irAEs With Adoptive T-Cell Therapy of PD-L1 expression, infiltration of effector T cells, and mutational
The adoptive transfer of T cells is generally well tolerated, but landscape. 70,93,94 However, it is unlikely that a single biomarker
it may be associated with the occurrence of life-threatening irAEs. will predict clinical outcome to immunotherapy; therefore, it
Serious irAEs after adoptive T-cell therapy may occur when T will be necessary to integrate multiple biomarkers in immune
cells targeting differentiation antigens in the tumor also recognize monitoring studies. Additionally, immune monitoring studies
these antigens on normal cells. For example, patients with should include gene expression studies, epigenetics studies, flow
melanoma who receive adoptive T-cell therapy with T cells that cytometry and CYTOF studies, immunohistochemical studies,
target differentiation antigens such as MART-1 and gp100 may mutational load studies, neoantigen studies, and microbiome
develop vitiligo and uveitis as irAEs, since these antigens are also studies. Sufficient access to longitudinal patient samples will be
expressed on normal cells. 86,87 Additionally, patients with meta- required to conduct these types of studies.
static RCC who were treated with carbonic anhydrase-IX
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(CAIX)-specific CAR T cells developed liver toxicity. In addition, Combination Therapy
fatal irAEs were reported in cancer patients who received anti- Immune checkpoint therapy has resulted in durable clinical
MAGE-A3 TCR-transduced T cells. 89 responses, but in only a fraction of patients. On the basis of the
Adoptive T-cell therapy with CAR T cells may also be associ- encouraging results with monotherapy, combination treatment
ated with another potentially life-threatening toxicity termed strategies are being explored extensively. 95
as cytokine release syndrome (CRS). The hallmark of CRS is Because anti-CTLA-4 and anti-PD-1 antibodies have distinct
elevated circulating levels of cytokines—including IL-6, TNF-α, mechanisms of action, preclinical studies evaluated combination
and interferon-γ—resulting in fever, rigors, hypotension, and treatment with anti-CTLA-4 and anti-PD-1/PD-L1, which
hypoxia. 90,91 demonstrated improved antitumor immune responses. 31,96
Treatment of irAEs associated with adoptive T-cell therapy, A detailed study in preclinical tumor models demonstrated
such as uveitis and colitis, can often be managed with topical that treatment with a combination of anti-CTLA-4 and anti-PD-1
or systemic corticosteroids; as for CAR T-cell therapy–related antibodies improves antitumor immunity and synergistically
CRS, it is generally managed with either high-dose corticosteroids eradicates tumors, and this synergy relies on the interdependence
or agents such as tocilizumab (an IL-6 receptor-blocking between IL-7 and IFNγ signaling in T cells; the lack of either
antibody). 92 pathway abrogates the therapeutic effects of this combination
therapy. 31
PERSPECTIVES ON FUTURE DEVELOPMENTS In 2015 the FDA approved the first combination immuno-
therapy of nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4)
Recent success with immunotherapy in the management of cancer for patients with previously untreated and unresectable metastatic
has given credence to the long-held belief that the immune system melanoma. 82,97 Patients receiving this combination had an objec-
can be used to treat cancer. However, the current immunothera- tive response rate of 50%. Importantly, this combination was
peutic strategies form only the tip of the iceberg in terms of effective irrespective of the PD-L1 expression. Several other
potential targets and combinations that can serve to improve combination therapies are currently being tested in clinical trials
clinical responses. A large number of additional agonistic and (ClinicalTrials.gov).
antagonistic mAbs that target immune checkpoints, as well as Combination treatments with immune checkpoint therapy
costimulatory molecule to potentiate T cell–mediated immune plus targeted therapy (angiogenesis inhibitors, tyrosine kinase
responses, are in various stages of clinical development; these inhibitors, BRAF inhibitors) also hold promise for improved
include antibodies against ICOS, OX40, 4–1BB, LAG-3, and VISTA efficacy. A phase I trial (NCT01472081; ClinicalTrials.gov)
(ClinicalTrials.gov). Furthermore, intense clinical investigation investigating the combination of nivolumab with sunitinib (a
is currently ongoing for the development of effective anticancer receptor tyrosine-kinase inhibitor) demonstrated tumor regression
98
vaccines and adoptive cell transfer strategies (ClinicalTrials.gov). in patients with metastatic RCC. The safety and efficacy of
another tyrosine-kinase inhibitor (lenvatinib) in combination
with pembrolizumab (anti-PD-1) are currently being explored
in a phase I/II study (ClinicalTrials.gov).
Another interesting combination currently being evaluated
ON ThE hOriZON BOX is radiotherapy plus immunotherapy. Several studies have
• Develop optimal patient selection strategy for cancer demonstrated that radiotherapy supports tumor-specific immu-
immunotherapy nity by enhancing antigen presentation and increasing the vulner-
• Develop the most appropriate timing for cancer immunotherapy ability of tumor cells to T cell–mediated attack. 99,100 Therefore
• Maximize cancer therapy effectiveness through strategies for: combination therapy with radiation plus immune checkpoint
• Developing combined immunotherapeutic approaches therapy or other immunotherapeutic strategies is warranted.
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• Optimally integrating standard anticancer modalities with
immunotherapy A phase I trial of hypofractionated radiotherapy in combination
with MEDI4736 (an anti-PD-L1 antibody) and tremelimumab