Page 1077 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1042 ParT EighT Immunology of Neoplasia

and ofatumumab targeting CD20 (for the treatment of CLL human IL-10 (AM0010) is being investigated in patients with
patients refractory to fludarabine and alemtuzumab). advanced solid tumors. 66
However, certain properties of cytokines pose significant
Conjugated/Tagged/Labeled/Loaded mAbs clinical challenges in achieving antitumor responses. Some
These mAbs target a molecule or antigen expressed on tumors cytokines are pleiotropic and act on several immune cells and
and are coupled to a cytotoxic or radioactive agent to enable mediate opposite effects. High-dose IL-2 is known to promote
delivery of a toxic substance directly to the tumor site. Treatment cytotoxic activity of effectors (CD8 T cells and NK cells) and
with a radiolabeled mAb is termed radioimmunotherapy (RIT). differentiation of CD4 T cells into T helpers. However, IL-2
Ibritumomab tiuxetan is a radiolabeled mAb against the CD20 can also preferentially expand Tregs due to a higher affinity to
antigen expressed on B lymphocytes and is FDA approved to the IL-2 receptor (CD25) on these cells. Sometimes multiple
treat different lymphomas. A randomized phase III trial comparing cytokines have the same functional effect, leading to redundancy
ibritumomab tiuxetan to rituximab in patients with relapsed or of cytokine signaling; therefore the therapeutic manipulation of
refractory NHL demonstrated a higher overall response rate (80% cytokines can be challenging, as the modification of one cytokine
versus 56%) and complete response (CR) rate (30% versus 16%) can be compensated by another cytokine. 65
for ibritumomab tiuxetan, but similar time to disease progression
for both treatment groups. 62 CANCER VACCINES
A different approach that uses mAbs coupled to chemothera-
peutic agents is known as antibody-drug conjugates (ADC). Efforts to produce effective anticancer vaccines have been ongoing
Brentuximab vedotin (Zevalin) is a mAb conjugated to a chemotoxic for decades. The two known categories are preventive cancer
drug called monomethyl auristatin E (MMAE), targeting the cell vaccines and therapeutic cancer vaccines.
membrane antigen CD30 on lymphocytes. A phase II clinical study Preventive vaccines consist of those that target infectious
(NCT00848926; ClinicalTrials.gov) with brentuximab vedotin in organisms that can cause cancer such as strains of HPV, which
patients with refractory Hodgkin lymphoma demonstrated contribute to the development of some head/neck cancers, anal
complete remission in 34% of patients, partial remission in 40% cancers, and cervical cancers. The three FDA-approved vac-
63
of the patients, and tumor regression in 94% of patients. Bren- cines include Cervarix HPV (against HPV-16,-18, -31,-33,-45),
tuximab vedotin is FDA approved to treat Hodgkin and anaplastic Gardasil (against HPV-6,-11,-16,-18), and Gardasil 9 (against
large-cell lymphoma. Trastuzumab emtansine (T-DM1) is another HPV-6,-11,-16,-18,-31,-33,-45,-52,-58). 67
example of an antibody-drug conjugate, which is FDA approved For the treatment of established cancers, sipuleucel-T was
for the treatment of HER2-positive breast cancer. 61 the first vaccine to be FDA approved. It is a cell-based vaccine
consisting of autologous peripheral blood mononuclear cells
Bispecific Monoclonal Antibodies (PBMC), which are collected from each patient and activated
These mAbs are formed by coupling two different mAbs together ex vivo with a recombinant fusion protein PA2024 (consisting
and allowing the construct to bind to two separate proteins of a prostate antigen and prostatic acid phosphatase fused to
simultaneously, thus enabling the mAb to direct the immune GM-CSF) before reinfusion into the patient. A phase III clinical
system to act against the tumor. trial demonstrated significant improvement in median OS after
Blinatumomab is one such example where one part of the treatment with sipuleucel-T in asymptomatic men with castrate-
mAb binds to the CD19 protein expressed on B-lineage acute resistant prostate cancer. Treatment with sipuleucel-T also resulted
lymphoblastic leukemia cells, while the second part of the mAb in an improvement in the rate of 3-year survival in 31.7% of
67
binds to the CD3 protein found on T cells, thereby linking these patients compared with 23.0% for those receiving placebo. The
two cell types to activate the T cell to exert cytotoxicity on the exact mechanism of action for sipuleucel-T remains to be defined.
+
CD19 tumor cells. Blinatumomab was first approved by the
FDA in 2014, based on the observations of a phase II trial in ONCOLYTIC VIRUS IMMUNOTHERAPY
patients with relapsed or refractory acute lymphoblastic leukemia
in which 40% of patients achieved a CR or complete response Oncolytic viruses represent a new class of therapeutic agents
with partial hematologic recovery (CRh). 64 that promote antitumor immune responses, which depend on
mechanisms that elicit selective tumor cell killing and induction of
CYTOKINE THERAPY systemic antitumor immunity. A variety of native and genetically
modified viruses are being developed and clinically investigated
Cytokines are low-molecular-weight proteins or glycoproteins as oncolytic agents. 68
that mediate cell-to-cell communication and play a pivotal role IMLYGIC (talimogene laherparepvec, T-VEC) was the first
in regulating biological activities, including innate immunity, oncolytic viral therapy to receive FDA approval for the treatment
adaptive immunity, inflammation, and hematopoiesis. of unresectable cutaneous and subcutaneous and nodal lesions
IL-2 and IFN-α have been used previously to treat patients recurrent after surgery in melanoma patients. IMLYGIC dem-
with metastatic melanoma and RCC. However, due to the onstrated improved median OS in a phase III study in patients
69
nonspecific activation of the immune response and the toxicities with advanced melanoma. IMLYGIC is a genetically modified
associated with these cytokines, as well as the development of herpes simplex virus type designed to selectively replicate within
novel immunotherapy agents as discussed above, the use of the tumor cells and induce lysis.
high-dose IL-2 and IFN-α has diminished in clinical practice.
Additional cytokines, including granulocyte macrophage–colony- CLINICAL CHALLENGES IN IMMUNOTHERAPY
stimulating factor (GM-CSF), IL-7, IL-12, IL-15, IL-18, and IL-21,
have also been investigated in clinical studies for patients with Multiple challenges that remain for immunotherapy agents include
65
advanced cancers. Currently, the antitumor activity of PEGylated resistance mechanisms and immune-related adverse events.