shutterstock_410170738.jpgCheckpoint inhibitors (CPIs) and chimeric antigen receptors (CAR-Ts) have transformed the field of cancer immunotherapy over the past five years. So far, these therapeutic approaches have operated in mutually exclusive landscapes with CPIs focusing on solid tumors and CAR-Ts focusing on hematologic malignancies, but now they’re entering each other’s spaces. As PD-1/L1 therapies enter hematology, and as CAR-Ts expand into solid tumors, should we expect a showdown at the immuno-oncology corral? 

In the short term, the answer is probably not, and in the longer term, there may be some synergy between the two approaches in solid tumors. While each approach offers transformative potential, they also play very specific roles in boosting the immune system.

The interface of immunology and oncology has been well documented, and immunotherapy has a long-standing history in hematologic malignancies via stem cell transplantation. In a 2013 article in the journal Immunity—“Oncology Meets Immunology: The Cancer-Immunity Cycle”—the authors proposed a framework of seven critical steps in the immunity cycle; this framework is critical to understanding how cancer evades the body’s natural defenses. Using this framework, it’s clear that both CAR-Ts and CPIs have complementary but distinct roles in immunotherapy. While CPIs aim to prevent tumor immunosuppression and facilitate an anti-tumor immune response, CAR-Ts are genetically modified T-cells that enable recognition of cancer cells.

The cancer-immunity cycle concept extends to hematologic malignancies as well, and we can see evidence of this across the numerous CPI and CAR-T trials. Where are companies placing their bets, and who should we expect to win? To help answer this question, we’ve summarized the clinical trial landscape for all phase I/phase II, phase II and phase III trials with at least 20 patients. 

Tumor

CAR-T Trials

PD-1/L1 Trials

Acute lymphoblastic leukemia

13

2

Chronic lymphocytic leukemia

7

4

Myelodysplastic syndromes

-

5

Acute myeloid leukemia

2

6

Hodgkin lymphoma

1

6

Diffuse large B-cell lymphoma

4

7

Mediastinal large cell lymphoma

NA

NA

Follicular lymphoma*

2

7

T-Cell lymphoma**

-

4

Multiple myeloma

3

12

 Source: Citeline, March 2017

In the short term (the next three to five years), there doesn’t appear to be a lot of overlap in the types of targets and, therefore, the types of cancer that the two approaches will address. The primary points of competition appear to be chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL).

In CLL, we believe that it will be challenging for either PD-1/L1 or CAR-T therapy to have a significant impact. Novel therapies have already dramatically transformed the treatment landscape of CLL over the past five years. Starting with the introduction of the BR regimen, and then followed by ibrutinib, venetoclax and obinutuzumab, patients have more good options than ever before.

This begs the question: What’s the real unmet need in this disease, especially when you consider that many patients follow an indolent disease course? Unless CAR-T and PD-1/L1 therapies can offer something looking like a real cure, or serve a biomarker-directed population, they likely will be reserved for the most aggressive cases or refractory disease, where unmet needs remain high.

In DLBCL, the story is a little more nuanced. DLBCL itself is quite heterogeneous with multiple variants and subgroups that inform different risk levels and prognostic outcomes. The early trials with PD-1/L1 have demonstrated mixed results in terms of overall response rate, but some patients have shown highly durable responses. Despite these results, there remains an interest in studying PD-1/L1 combinations in this disease, especially in combination with lenalidomide.

On the flip side, Kite Pharma’s Zuma trial recently reported a 36% overall response rate with 31% complete responders in relapsed disease. This is a promising result in a patient population with high unmet need. The fact remains that R-CHOP therapy remains curative for 60% of patients in front-line therapy, so it may be challenging for either approach to sway physicians from this “gold standard” of care. 

Of course, the real winners will be the patients. While it may sound cliché, it also happens to be true. To quote Phillipe Armand from the Dana Farber Cancer Institute, “We are at the dawn of a new day in [hematologic malignancy] immunotherapy”—and it’s a privilege to get to play even a small part in it.  


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*Number of trials taking place for FL and DLBCL involves duplicate counting as same clinical trial includes population for different sub-indications within NHL

** Cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)

Chart notes:

  1. Includes total number of ongoing trial (open enrollment, closed enrollment, temporary close) worldwide. Planned, completed and terminated trials have not been considered for the pipeline trials
  2. Total number of clinical trials for each of the indications are irrespective of sponsors (industry, academic, government)

 

Topics: oncology, cancer, Malik Kaman, CAR-T, immunotherapy, immuno-oncology, CPI