Immunotherapy! Targeted therapy! TIL! CARs! Intratumoral therapies! Here we go!!!!
Novel
Checkpoints and Cosignaling Molecules in Cancer Immunotherapy. Giuroiu, Weber. Cancer J. 2017 Jan/Feb.
The
recent demonstration of the antitumor efficacy of checkpoint protein
inhibition has resulted in the approval of blocking antibodies
against the programmed cell death 1 (PD-1)/programmed cell death
ligand 1 (PD-L1) pathway in multiple different histologic findings.
Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung
cancer have been followed by approvals in bladder, renal, and head
and neck cancers and Hodgkin lymphoma, with others undoubtedly to
come. However, PD-1 is only one of many checkpoints and agonistic
regulatory molecules expressed on T cells by which maintenance of the
balance between costimulatory and coinhibitory signaling pathways is
perturbed in cancer. The manipulation of many of these molecules in
cancer patients might be associated with clinical benefit. The
majority of the T-cell cosignaling receptors belong to either the
immunoglobulin superfamily or the tumor necrosis factor receptor
superfamily. A total of 29 immunoglobulin superfamily and 26 tumor
necrosis factor receptor superfamily cosignaling receptors have been
identified that are expressed on T cells, providing fertile ground
for development of inhibitory or agonistic antibodies and small
molecules as cancer therapeutics. In the current work, we focus on
some of the most promising new checkpoints and agonistic or
cosignaling molecules that are in early clinical development as
single agents or in combinations with PD-1/PD-L1, cytotoxic
T-lymphocyte-associated protein 4 blockade, or chemotherapy with an
emphasis on those that have reached the clinic and on important
targets that are in late preclinical development.
Novel Targeted
Therapies for Metastatic Melanoma. Iams, Sosman, Chandra. Cancer J. 2017 Jan/Feb.
Oncogene-targeted
therapy is a major component of precision oncology, and although
patients with metastatic melanoma have experienced improved outcomes
with this strategy, there are a number of potential therapeutic
targets currently under study that may further increase the drug
armamentarium for this patient population. In this review, we discuss
the landscape of targeted therapies for patients with advanced
melanoma, focusing on oncogene mutation-specific targets. In patients
with typical BRAF V600-mutant melanoma, combination BRAF and MEK
inhibition has surpassed outcomes compared with monotherapy with BRAF
or MEK inhibition alone, and current strategies seek to address
inevitable resistance mechanisms. For patients with NRAS-mutant
melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6
inhibition are burgeoning strategies; for patients with KIT-mutant
melanoma, tyrosine kinase inhibition is being leveraged, and for
NF-1-mutant melanoma, mTOR and MEK inhibition is being actively
evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma,
MEK inhibitor monotherapy is the potential novel targeted approach on
the horizon. For advanced uveal melanoma, novel targets such as
IMCgp100 and glembatumumab have shown activity in early studies. We
review additional strategies that remain in the preclinical and early
clinical pipeline, so there is much hope for the future of targeted
agents for distinct molecular cohorts of patients with advanced
melanoma.
Adoptive Cell
Therapy for Metastatic Melanoma. Merhavi-Shoham, Itzhaki, Markel, et al. Cancer J. 2017 Jan/Feb.
Adoptive
cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a
powerful form of immunotherapy by inducing durable complete responses
that significantly extend the survival of melanoma patients.
Mutation-derived neoantigens were recently identified as key factors
for tumor recognition and rejection by TILs. The isolation of T-cell
receptor (TCR) genes directed against neoantigens and their
retransduction into peripheral T cells may provide a new form of
ACT. Genetic modifications of T cells with chimeric antigen receptors
(CARs) have demonstrated remarkable clinical results in hematologic
malignancies, but are so far less effective in solid tumors. Only
very limited reports exist in melanoma. Progress in CAR T-cell
engineering, including neutralization of inhibitory signals or
additional safety switches, may open opportunities also in
melanoma.We review clinical results and latest developments of
adoptive therapies with TILs, T-cell receptor, and CAR-modified T
cells and discuss future directions for the treatment of melanoma.
Intratumoral Approaches for the Treatment of
Melanoma. Bommareddy, Silk, Kaufman. Cancer J. 2017 Jan/Feb.
There have been significant advances
in the immunotherapy of melanoma over the last decade. The tumor
microenvironment is now known to promote an immune-suppressive milieu
that can block effective immune-mediated tumor rejection. Several
novel strategies designed to overcome local immunosuppression hold
promise for treatment of melanoma and other cancers. These approaches
include oncolytic viruses, plasmid DNA delivery, Toll-like receptor
agonists, inflammatory dyes, cytokines, checkpoint inhibitors,
immunomodulatory agents, and host and pathogenic cell-based vectors.
In addition, there are several novel methods for local drug delivery,
including direct injection, image-guided, electroporation, and
nanodelivery techniques under study. The approval of talimogene
laherparepvec (Imlygic), an attenuated, recombinant oncolytic
herpesvirus, for melanoma treatment is the first intratumoral agent
to receive regulatory approval for the treatment of patients with
melanoma. This review will focus on the rationale for intratumoral
treatment in melanoma, describe the clinical and safety data for some
of the agents in clinical development, and provide a perspective for
future clinical investigation with intratumoral approaches. Melanoma
has been a paradigm tumor for progress in targeted therapy and
immunotherapy and will likely also be the tumor to establish the
therapeutic role of intratumoral treatment for cancer.
Sounds good! I like a multi-faceted approach. Now! Let's make it so! Double time!!!! - c
