For Hodgkin Lymphoma, PD-1 Blockade Is Not the Final Answer

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Stephen M. Ansell, MD, PhD

Stephen M. Ansell, MD, PhD

Although programmed cell death protein 1 (PD-1) blockade is highly effective in Hodgkin lymphoma, not all patients respond, and not all responses are durable. Stephen M. Ansell, MD, PhD, Chair of the Mayo Clinic Lymphoma Group and Professor of Medicine at the Mayo Clinic, Rochester, described novel strategies to further manipulate the immune system in a presentation at the 2018 Pan Pacific Lymphoma Conference in Maui.1

PD-1 Inhibition Is Effective, but…

Hodgkin lymphoma is sensitive to inhibitors of PD-1 and its programmed cell death ligand 1 (PD-L1), but there must be other means of energizing T cells, “to wake the cell up, get the cell to do its job,” that would improve outcomes in patients, Dr. Ansell said. Highlighting the robust activity of anti–PD-1 agents in this cancer, he described a patient who responded promptly to nivolumab (Opdivo) in the original phase I trial.

“He called me from the car on the way home [from treatment], saying ‘It’s working!’ I asked him how he knew this, and he said, ‘I’m not itching anymore, and I feel better.’ As it turned out, he was right. He’s still in remission 5 years later.”

Per the trial protocol, the drug was stopped after 2 years of treatment. The patient’s disease progressed -within 8 months; he was re-treated with -nivolumab, went back into remission, and has since remained on the drug.

Using an antibody-drug conjugate to kill the tumor cell at the same time as optimizing the immune response may be a very good strategy for going beyond PD-1 blockade.
— Stephen M. Ansell, MD, PhD

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Although this was an impressive response, Dr. Ansell acknowledged that as an immunologist, he was “disappointed” that the patient had disease progression after anti–PD-1 treatment. Disease progression indicated a lack of immunologic memory—the creation of memory cells that could again recognize the antigen and kill it promptly. “Nivolumab didn’t do that,” he said, a finding that suggested patients may need lifelong treatment and that a single immune checkpoint inhibitor may not be sufficient.

Long-term data from a phase II trial have recently shown that about 70% of patients with Hodgkin lymphoma benefit from pembrolizumab (Keytruda) and nivolumab,2,3 but a point of concern, for Dr. Ansell, is that the progression-free survival curves may not be plateauing. “As time goes by, patients are slowly progressing, telling us we did something right but didn’t really fix the problem,” he said. “We need to be thinking beyond immune checkpoints by themselves.”

Learning From the Data

Dr. Ansell summed up the key lessons learned from the initial studies of PD-1/PD-L1 blockade, which will be taken into consideration going forward:

  • PD-1/PD-L1 blockade is effective in the majority of patients, but responses are not durable long-term.
  • The Reed-Sternberg cell has essentially created its own specialized microenvironment, marked by an abundance of PD-L1–positive macrophages that express high levels of PD-L1. This has a significant inhibitory effect and prevents the effector cells from reaching the tumor.
  • In classic Hodgkin lymphoma, most patients have a copy gain or amplification of the 9p24.1 locus, resulting in overexpression of PD-L1 and PD-L2. However, this is associated with response to PD-1/PD-L1 blockers; the message is that patients with very high levels of PD-L1 expression are the ones most likely to benefit most from immune checkpoint inhibition.
  • PD-L1 is actually secreted into the bloodstream, so PD-L1 expression can affect distant sites away from the tumor. It could be important not only to block PD-L1 at the tumor site, but in the macroenvironment and throughout the whole patient.

Beyond PD-1/PD-L1 Blockade: Combination Therapies?

On this fourth point, clues can be taken from immune checkpoint inhibition in solid tumors, such as combining anti–PD-1/PD-L1 blockade with cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade. Drugs such as ipilimumab (Yervoy) disrupt the CTLA-4 pathway, thus inducing antitumor immunity. Drugs such as nivolumab disrupt the PD-1–pathway signaling and restore antitumor T-cell function. Blockade then occurs at the tumor/T-cell interface and in other areas where the antigen is presented (such as lymph nodes), he explained.

“This might be a good two-for-one way to build upon PD-1 blockade,” he noted. “But although the results are interesting in Hodgkin lymphoma, I’m not exactly sure they are a step forward.”

In a small phase I trial in patients with classic Hodgkin lymphoma, led by Dr. Ansell, the combination of nivolumab and ipilimumab yielded an overall response rate of 74%.4 Whether this is “dramatically different” from single-agent nivolumab remains a question. “That will take a randomized trial to show. There may be some modest increase in benefit, but certainly not on the scale as was seen in melanoma and other diseases,” he pointed out.

Macrophages are part of the moat that surrounds and protects the Reed-Sternberg cell. How about getting them engaged in this process?
— Stephen M. Ansell, MD, PhD

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Another approach to moving beyond checkpoint blockade is to use anti–PD-1 agents with brentuximab vedotin (Adcetris). “What you’re doing is delivering this antibody-drug conjugate to the tumor cell, and as the tumor cell dies, it releases neoantigens, which are then ‘mopped up’ by macrophages, and dendritic cells are shown to the immune system. You get increased cell death, increased presentation of tumor antigens, and increased T-cell activation, and thereby a better result,” he explained.

This approach seems to be somewhat effective. In a study of 29 patients, the overall response rate was 90%, and 62% were complete molecular responses.5 The assessment of durability was confounded by the fact that many patients went on to transplant. A second small study of 12 relapsed patients showed a response rate of 100%, and a complete response rate of 66%.6

“This combination looks promising,” he commented. “Using an antibody-drug conjugate to kill the tumor cell at the same time as optimizing the immune response may be a very good strategy for going beyond PD-1 blockade.”

Beyond PD-1/PD-L1 Blockade: Upfront Treatment?

Clinical trials are also now evaluating checkpoint inhibitors earlier in the disease course. In one ongoing study, newly diagnosed patients with advanced-stage disease receive four doses of single-agent nivolumab followed by six cycles of nivolumab plus chemotherapy. After four doses of nivolumab alone, responses have been seen in about two-thirds of patients—this is similar to the activity seen with nivolumab in patients who relapse post-transplant, he noted.

By the end of treatment in this study, the overall response rate by investigator review was 84%, with 80% being complete responses. “This looks promising. Giving chemotherapy at the same time as PD-1 blockade might be an answer,” he offered, “but this will need to be compared head to head with standard chemotherapy, as those results can also be very good.”

Novel Harnessing of Other Immune System Components

Another approach is to enlist other components of the immune system in targeting the malignant cell. This is the goal of bispecific antibodies, such as AFM13, a first-in-class compound that targets CD30 on the Reed-Sternberg cell and CD16A on natural killer cells. Although response rates to the single agent were fairly modest in a phase I study by the German Hodgkin Lymphoma Study Group,7 the best use of this approach and other bispecific antibodies may be in combination with PD-1 blockade, the data for which are just starting to mature, he said.

“Getting the tumor cell engaged with natural killer cells and T cells at the same time might be a further way in which we can move beyond immune checkpoint therapy,” he commented.

Yet another way to manipulate the immune cells is by blocking CD47-SIRP-α signaling, which is involved in macrophage activation. “Macrophages are part of the moat that surrounds and protects the Reed-Sternberg cell. How about getting them engaged in this process? Couldn’t there be a way to get them to kill the tumor cell they are supposed to be protecting?” he asked.

Macrophages recognize prophagocytic (ie, “eat me”) signals on tumor cells and proceed to consume those cells. Tumor cells protect themselves, however, with a “don’t eat me” signal; CD47 on the cell surface is one of them. When CD47 binds to SIRP-α, the macrophage acknowledges the “don’t eat me” signal and gives the cell a pass.

“You can block this process. You can get the macrophage to do its job on the cell that needs to be ‘eaten,’” he said. This can be accomplished with CD47-directed antibodies and SIRP-α decoy molecules that block the inhibitory CD47 signal.

Early studies of TTI-621, an immune checkpoint inhibitor targeting CD47, showed the drug to be well tolerated in patients with various hematologic malignancies, although dose-dependent and transient decreases in hemoglobin and platelets were seen.8 “We can’t yet tell if this is an effective therapy in Hodgkin lymphoma, but I think getting the innate immune system to participate with the adaptive immune system is one of the ways moving forward,” Dr. Ansell said. “There are now trials utilizing the inhibition of ‘don’t eat me’ at the same time as inhibition of PD-1.”

Dr. Ansell did not discuss the more familiar chimeric antigen receptor (CAR) T-cell therapy but emphasized it is obviously a strategy that should be studied in Hodgkin lymphoma. “I think brand new bispecific antibodies and macrophage-directed approaches are going to be the future in combination as we go beyond immune checkpoint therapy,” he concluded. ■

DISCLOSURE: Dr. Ansell reported no conflicts of interest.


1. Ansell SM: Beyond checkpoint inhibitors for Hodgkin lymphoma. 2018 Pan Pacific Lymphoma Conference. Invited Lecture. Presented July 19, 2018.

2. Armand P, et al: Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation. J Clin Oncol 36:1428-1439, 2018.

3. Chen R, et al: Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 35:2125-2132, 2017.

4. Ansell S, et al: A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). 2016 ASH Annual Meeting. Abstract 183. Presented December 5, 2016.

5. Herrera AF, et al: Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. 2016 ASH Annual Meeting. Abstract 1105. Presented December 5, 2016.

6. Diefenbach CS, et al: A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma. 2016 ASH Annual Meeting. Abstract 1106. Presented December 5, 2016.

7. Rothe A, et al: A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 125:4024-4031, 2015.

8. Ansell S, et al: A phase I study of TTI-621, a novel immune checkpoint inhibitor targeting CD47, in patients with relapsed or refractory hematologic malignancies. 2016 ASH Annual Meeting. Abstract 1812. Presented December 6, 2016.