Using the power of the human immune system to combat cancer has been a long-standing goal in oncology. In the last few years, an important milestone on the way to this goal has been the understanding of immune checkpoint pathways. Checkpoint pathways modulate the function of immune effector cells, especially T cells. The most important checkpoint pathways identified to date are the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. Both of these pathways inhibit the function of T cells when a checkpoint receptor (CTLA-4 or PD-1) is engaged by its ligands (B7-1 and B7-2 for CTLA-4, PD-L1 and PD-L2 for PD-1). By expressing the ligands of checkpoint receptors on their surface, human tumors can inhibit T cells and evade immune attack.
The availability of monoclonal antibodies targeting different checkpoint receptors or ligands now allows us to interfere with cancer immune evasion strategies. Indeed, those antibodies have already had important therapeutic successes and achieved regulatory approval in several non-hematological cancers including melanoma, lung cancer, renal cell cancer, bladder cancer, and head and neck cancer. Among all possible targets for checkpoint blockade, one tumor type stood out as being potentially highly vulnerable: classical Hodgkin lymphoma (cHL). Work done in the lab of Dana-Farber’s Margaret Shipp, MD, has shown that cHL nearly always harbors genetic abnormalities at the 9p24.1 chromosomal location, resulting in overexpression of the PD-1 ligands PD-L1 and PD-L2. This makes cHL unique among all tumors in having a genetically hardwired dependence on the PD-1 pathway for survival, and therefore potentially an intrinsic vulnerability to PD-1 blockade.
Multiple clinical trials have tested and confirmed this hypothesis. Two phase 1 trials of PD-1 blockade tested the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab in heavily pre-treated cohorts of patients with relapsed/refractory (R/R) cHL. The overall response rates were 87% and 65%, respectively, with many responses that continued after 18-24 months of follow-up (Ansell et al, NEJM 2015; Armand et al, JCO 2016). Furthermore, two phase 2 studies have now completed enrollment and have confirmed this finding in specific populations of patients with R/R cHL. In both cases, results released to date (Younes et al, Lancet Oncology 2016; Moskowitz et al, ISHL 2016; Zinzani et al, ISHL 2016) support the phase 1 findings, with response rates of 65-75% and with a majority of patients (>90%) obtaining some tumor shrinkage. Based on these results, the FDA has granted accelerated approval to nivolumab and breakthrough designation to pembrolizumab in R/R cHL. Ongoing and future trials will test the possible benefit of using PD-1 blockade, alone or in combination with other therapy, earlier in the treatment of patients with cHL.
Figure 1: from Armand, Immune Checkpoint Blockade in Hematologic Malignancies, Blood, 2015
PD-1 and CTLA-4. This figure shows a simplified representation of the function of the PD-1 and CTLA-4 immune checkpoint pathways. APC, antigen-presenting cell; TCR, T-cell receptor; MHC, major histocompatibility complex; CD, cluster of differentiation; IL-2, interleukin-2; PD-1, programmed death-1; CTLA-4, cytotoxic T-lymphocyte associated protein 4; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif.
Figure 2: from Younes et al, Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial, Lancet Oncology, 2016
IRRC-assessed outcomes. (A) Best change from baseline in target lesion for all response-evaluable patients. The dashed line indicates 50% reduction in target lesion. Negative values indicate maximum tumour reduction, and positive values indicate minimum tumour increase.