Here is part of the editorial from the NEJM. There is a big difference between Bavi
and this anti-PD-1 antibody. Bavi targets the tumor vasculature through PS.
Macrophages then bind to Bavi and phagocytose (eat) the attached endothelial cells thus
destroying the blood vessels feeding the tumor. There are also a bunch of things Bavi
does to reverse the immunosuppression in the tumor microenvironment. The main
point is Bavi enables the innate immune response (macrophages) to destroy the tumor,
whereas the anti-PD-1 mAb enables T-cells, and hence the adaptive immune response.
Bavi also has the ability to enable T-cells which can lead to long-term immunity.
I think these results for anti-PD-1 are very important in showing that cancer immunotherapy works!
Tumor Immunotherapy Directed at PD-1
Antoni Ribas, M.D., Ph.D.
The treatment of cancer by harnessing immune
responses has long been pursued. Efforts to turn
on the immune system against cancers with inactivated
tumor vaccines or intratumor injections
of bacterial products to induce local inflammation
and recruit an antitumor immune response
have led to anecdotal successes. Increasing knowledge
about how the immune system is activated,
coupled with advances in recombinant DNA technology,
has allowed the clinical testing of immune-
stimulating cytokines such as interferons
and interleukins. These trials have led to a low
frequency of durable tumor responses in selected
cancers such as melanoma and renal-cell carcinoma
at the expense of serious toxic effects. The
finding that dendritic cells play a central role in
orchestrating a T-cell response to cancer has resulted
in multiple clinical trials of dendritic-cell–
based vaccines. These studies again provided evidence
of occasional tumor responses in a minority
of patients.1
A major limitation of the various approaches
to turning on an immune response to cancer is
that the immune system exerts a major effort to
avoid immune overactivation, which could harm
healthy tissues. Cancer takes advantage of this
ability to hide from the immune system by exploiting
a series of immune escape mechanisms
that were developed to avoid autoimmunity.
Among these mechanisms are the hijacking of
immune-cell–intrinsic checkpoints that are induced
on T-cell activation.2
Blockade of one of these checkpoints, cytotoxic
T-lymphocyte–associated antigen 4 (CTLA-4), provided
the first evidence of improvement in overall
survival for the treatment of patients with
metastatic melanoma.3,4 The coinhibitory receptor
CTLA-4 predominantly regulates T cells at the
stage of initial activation by competing with the
CD28+ costimulatory receptor for binding of CD80
(B7-1) and CD86 (B7-2) expressed by antigen-presenting
cells such as dendritic cells (Fig. 1).
CTLA-4 is expressed approximately 48 hours after
T-cell activation and provides dominant negative
signaling. Inhibition of CTLA-4 by blocking
antibodies such as ipilimumab or tremelimumab
results in objective response rates of 10 to 15%
in patients with metastatic melanoma, a response
that is associated with clinically significant inflammatory
or autoimmune toxic effects in 20 to
30% of patients.2
The programmed death 1 (PD-1) receptor is
another inhibitory T-cell receptor that is engaged
by its two known ligands, PD-L1 (also known as
B7-H1 or CD274) and PD-L2 (also known as B7-DC
or CD273), primarily within the tumor microenvironment
(Fig. 1).2,5 The increased selectivity for
immune suppressive signals that are delivered
directly by the cancer, together with the role of
PD-1 in regulating predominantly the effector
phase of T-cell responses, predicts that PD-1 inhibition
will have fewer side effects and greater
antitumor activity than CTLA-4 inhibition.2,6 PD-1
was discovered in 1992 by Honjo and colleagues,
who were studying mechanisms of T-cell death.6
Since then this immune regulatory receptor has
been shown to have a critical role in autoimmunity,
infectious immunity, transplantation immunity,
and allergy, in addition to the demonstration
of its blockade in tumor immunotherapy.7-9 PD-1
activities include the inhibition of T cells during
long-term antigen exposure, as happens in chronic
viral infections10 and cancer.2
AI
