Exploring CTLA-4 Blockade in Classical Hodgkin Lymphoma

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Treatment options for patients with multiply relapsed classical Hodgkin lymphoma (cHL) have changed dramatically in recent years with the approvals of brentuximab vedotin (BV) and the PD-1 monoclonal antibodies (mAbs), nivolumab and pembrolizumab. Since their initial approvals, these highly active agents are increasingly being used in earlier lines of therapy. As a result, many patients who relapse after autologous stem cell transplantation (ASCT) or who are not eligible for ASCT will have already received both BV and a PD-1 mAb and are left with limited treatment options. Therefore, novel and highly effective treatments are urgently needed for this group of patients.

cHL is characterized by a unique tumor microenvironment (TME) comprised of rare Reed-Sternberg (RS) cells and a more frequent, albeit ineffective population of infiltrating immune cells. The lab of Margaret Shipp, MD, at Dana-Farber Cancer Institute and others showed that alterations in PD-1 signaling (mediated by nearly universal genetic alterations in 9p24.1) are critical for RS cell immune evasion, and these findings spurred clinical investigation of PD-1 blockade in this disease.1

More recently, studies at Dana-Farber suggest that other immune checkpoints are also critical for maintaining the immunosuppressive microenvironment in cHL and could also be targeted using immunotherapy. Scott Rodig, MD, PhD, and colleagues at Dana-Farber Brigham Cancer Center found that the cHL tumor microenvironment (TME) is highly enriched for CTLA-4-positive T cells, which outnumber those expressing PD-1. Not only are CTLA-4-positive T cells more numerous than PD-1 positive T cells, but they are also more likely to be in direct contact with RS cells. In addition, the ligand for CTLA-4, CD86, is also frequently expressed in the cHL TME, both on RS cells and on tumor-associated macrophages.2

Figure 1: CTLA-4 is more frequently expressed than PD-1 within the cHL TME (left) and CTLA-4 positive T cells are enriched in close proximity to Hodgkin RS cells (right).

Based on these findings and earlier studies showing clinical responses with CTLA-4 blockade in cHL, 3,4 our Lymphoma Program has launched a phase 2 trial testing the CLTA-4 mAb, ipilimumab, in patients with multiply relapsed cHL. The trial includes two cohorts of patients who have had suboptimal responses to prior treatment with a PD-1 mAb. Both cohorts are currently enrolling patients (Figure 2).

  1. Cohort 1 is enrolling patients who have received at least 18 weeks of PD-1 mAb monotherapy and have failed to achieve a complete response. These patients will receive 4 cycles of nivolumab + ipilimumab followed by nivolumab maintenance therapy with the goal of deepening their response and prolonging their remission with immunotherapy.
  2. Cohort 2 is enrolling patients who have failed a PD-1 mAb. In this cohort, patients will receive ipilimumab monotherapy for 12 weeks. Afterwards, responding patients will continue ipilimumab maintenance therapy while non-responding patients will have the option of receiving combination therapy with both ipilimumab and nivolumab.
Figure 2: Ipilimumab Trial Schema

Beyond immune checkpoint blockade, other forms of immunotherapy are also being investigated for patients with cHL. Dana-Farber is also participating in an international phase II study of the CD30 chimeric antigen receptor (CAR) T cell, TT11, which we expect to open to enrollment by the end of 2022.


1. Roemer MGM, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J. Clin. Oncol. 2016;34(23):2690–7.

2. Patel SS, Weirather JL, Lipschitz M, et al. The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4- positive T-cells that are PD-1-negative. Blood. 2019;134(23):2059–2069.

3. Armand P, Lesokhin A, Borrello I, et al. A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Leukemia. 2020.

4. Davids MS, Kim HT, Costello, CL et al. A Multicenter Phase I/Ib Study of Ipilimumab for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation. NEJM. 2016.