Page 1780 - Hematology_ Basic Principles and Practice ( PDFDrive )

1584 Part IX Cell-Based Therapies

move to earlier stages of treatment. Additional studies are planned
and ongoing within HL.
T Cell
Stimulation Inhibition
Non-Hodgkin Lymphoma
CD27
ICOS TCR TIM-3 While PD-1 blockade has shown the most promise in HL, clinical
CD28 PD-1 activity has also been seen in multiple types of NHL including FL,
CD137 LAG3 CTLA-4
OX40 DLBCL, and T-cell lymphoma. Interest in CBT in NHL has been
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driven by the durable responses seen with ipilimumab, as well as
by an early study of pidilizumab in patients with R/R HMs that
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demonstrated an isolated CR in a patient with FL. Based on these
results, a phase II trial examined combination therapy with pidili-
zumab and rituximab in patients with rituximab-sensitive relapsed
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FL. Among 32 patients, the ORR was 66%, with a 52% CR rate.
While it is difficult to assess the activity of this combination without
a monotherapy control arm, these rates compare favorably with
historic controls treated with rituximab alone. In addition, immuno-
OX40L
CD137L MHC histochemical analysis showed that PD-1 expression was significantly
B7-1 B7-1 PD-L1 higher on T cells of responders, mechanistically supporting the role
ICOSL B7-2 B7-2 PD-L2 of PD-1 activity in the combination. Preliminary results from the
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CD70 Gal-9
previously mentioned phase 1 nivolumab trial (NCT01592370) also
demonstrated activity in FL and DLBCL with OR rates of 40% and
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36%, respectively. The underlying biology of PD-1 blockade in
Antigen-presenting cell these malignancies is less well understood. In general, FL is considered
to be one of the more immune sensitive HMs based on occasionally
Fig. 102.1 COSTIMULATORY AND INHIBITORY RECEPTORS. A witnessed spontaneous regressions and responsiveness to nonspecific
partial list of stimulatory and inhibitory T-cell coreceptors currently in clinical immune activators like bacillus Calmette-Guérin and interleukin-2.
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development with their cognate ligands. MHC, Major histocompatibility Because of this, it is an attractive target for PD-1 blockade and
complex; TCR, T-cell receptor. immune checkpoint blockade in general. Within DLBCL, PD-L1
expression appears to be restricted to a subset of tumors, as discussed
later, which could explain the activity seen with nivolumab. Larger
phase II studies in FL and DLBCL are ongoing. Lastly, the phase 1
results hinting at the potential therapeutic effectiveness of this nivolumab trial also demonstrated a 17% ORR in a mixed popula-
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approach. tion of T-cell NHLs. The significance of these findings is not yet
clear, but this represents an exciting new area of investigation for an
otherwise difficult to treat, chemorefractory group of malignancies.
Hodgkin Lymphoma
Among all HMs, there was particular interest in using PD-1 blockade Multiple Myeloma
in HL. HL is unique among lymphomas for its tissue architecture,
which is composed of relatively rare Reed-Sternberg (RS) tumor Multiple myeloma (MM) has been included in trials of PD-1
cells surrounded by a much larger population of immune infiltrat- blockade based on preclinical data showing PD-L1 expression on
ing cells that appear unable to generate an anti-RS cell activity. MM cells and PD-1 upregulation on immune cells in the MM
Genetic analyses of HL demonstrated frequent 9p24.1 amplification, microenvironment. 24,25 Despite these observations, early data obtained
driving increased expression of both PD-L1 and PD-L2, as well as with PD-1 blockade has been disappointing. In the phase 1 niv-
increased activity of the Janus activated kinase/signal transducer and olumab trial, no CRs or PRs were observed in 27 patients with MM;
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activator of transcription (JAK/STAT) pathway, which itself leads to however, 18 of 27 (67%) had stable disease lasting several months.
17
increased expression of PD-L1. Epstein-Barr virus (EBV) infection, CBT experience in solid tumors suggests that such stable disease may
which occurs relatively commonly in HL, is also associated with reflect antitumor activity and provide sustained periods of disease
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increased PD-L1 expression. These mechanisms explain the high control; more investigation is needed in MM to determine if there is
rates of PD-L1 and PD-L2 expression seen in HL and, additionally, indeed a true clinical benefit from CBT. Based on these early results,
suggest that this upregulation may be more fixed than in other PD-1 blockade is being investigated in early phase trials as part of
tumors. combination therapy with lenalidomide, pomalidomide, and a novel
Based on these observations, patients with HL were included in Bruton tyrosine kinase inhibitor (NCT02077959, NCT02289222,
independent expansion cohorts in two phase 1 trials examining PD-1 NCT02362035).
blockade with nivolumab (NCT01592370) and pembrolizumab
(NCT01953692) within a mixed group of patients with R/R HMs.
HL patients in both studies were heavily pretreated, with the majority Safety
having relapsed or progressed after brentuximab and autologous stem
cell transplantation. Despite this, CR rates of 17% and 21% and In the limited experience with PD-1 blockade in HMs, the safety
ORRs of 87% and 65% were seen with nivolumab and pembroli- profile of the drugs appears to be comparable with the more extensive
zumab, respectively. The durability of responses with single-agent experience in solid malignancies. IrAEs with PD-1 therapy appear
therapy have also been impressive with ongoing responses for greater to be less common than with CTLA-4 blockade, specifically with
than 1 year in many patients. Importantly, the mAbs in both trials lower rates of colitis and endocrinopathies. Within the phase 1
showed an acceptable safety profile in HL with limited irAEs and no nivolumab, the largest trial published thus far in HM, the rate of
drug-related grade 4 or 5 toxicities. 19,20 While these trials were small pneumonitis was around 10%, which is only slightly higher than
and merit confirmation, they have generated hope that PD-1 block- that seen in solid malignancies, despite high rates of prior treatment
ade could bring about a fundamental shift in the treatment of R/R with potentially pneumotoxic regimens (including radiation therapy
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HL. As more clinical data accumulate, PD-1 blockade will likely and brentuximab). Additional studies are clearly needed, but these