Researcher Evaluates Next Steps for Incorporating CAR T-Cell Therapy into Solid Tumor Space

Prasad S. Adusumilli, MD, FACS

Chimeric antigen receptor (CAR) T-cell therapy has made monumental strides in the treatment landscape for many hematologic malignancies, including leukemias and lymphomas. Based on the impressive outcomes observed in this setting, researchers are exploring the potential to move CAR T-cell therapy into the solid tumor treatment landscape.

The most progress with this cellular therapy has been with CAR T cells targeting CD19 in the leukemia and lymphoma treatment landscapes. However, CAR T cells operate differently in solid tumors and raise a number of challenges, including the tumor’s immune microenvironment.

To successfully utilize CAR T-cell therapy in patients with solid tumors, researchers must first come to understand how the tumor microenvironment plays a role. The CAR T cells need to be designed for a specific solid tumor as they can have heterogenous antigen expression, unlike in hematologic malignancies. Correlative studies must be conducted to help oncologists understand the changes in the tumor microenvironment, which will aid in the development of next-generation CAR T cells.

In an interview with Targeted Oncology, Prasad S. Adusumilli, MD, FACS, deputy chief of Thoracic Surgery, Vice Chair of Department of Surgery, Memorial Sloan Kettering Cancer Center, discussed how CAR T-cell therapy could play a role in the treatment of solid tumors. He highlighted the current research and next steps planned to move this cellular therapy into the solid tumor treatment landscape.

TARGETED ONCOLOGY: Could you start by providing a background to CAR T-cell therapies and how they have evolved in hematologic malignancies?

Adusumilli: Mostly for leukemia and lymphoma, targeting CD19 is where CAR T-cell therapy made its progress, where patients with therapy-resistant cancers like leukemia and lymphoma [achieved] complete responses that are durable. The next step is going to be translating this CAR T-cell therapy to the solid tumors.

TARGETED ONCOLOGY: Where does CAR T-cell therapy fit into the treatment landscape now for solid tumors?

Adusumilli: For solid tumors, it's in the stage of translating preclinical to early-stage clinical trials. Unlike hematological malignancies, there are several hurdles in solid tumors that are specific to the solid tumor immune microenvironment. That's where several researchers and investigators are focusing now to cross each of these hurdles and to learn how to translate this into solid tumors.

The challenges for solid tumors are that they notoriously do not let the effector T cells enter into the tumor, and especially when the CAR T cells or other T-cell therapies are delivered intravenously, these T cells get sequestered in the lung and slowly trickle down to the tumor. That makes for very few T cells entering into the tumor. One thing we have done to overcome is that to regionally administer intrapleural CAR T cells. We noticed, 1), that thereby we can avoid the pulmonary sequestration and 2), antigen activation lets the CD4s help the CD8; the helper function comes in early thereby CD8 CAR T cells can expand. The other factors that are known hurdle is the presence of stroma in the solid tumor that sequester the T cells and prevent them from entering into the tumor mass.

The solid tumor immune microenvironment is very immunosuppressive. What is well known and well-studied is PD-1/PD-L1 pathway where the checkpoint blockade works, but even the CAR T cells can get exhausted in the presence of overwhelming antigen presence. In addition, M2 macrophages, TGF beta, and T regulatory cells are a part of a solid tumor immune microenvironment. More importantly, when treating the patients with metastatic cancers, which we focus in phase 1 clinical trials, each organ metastases has a different immune microenvironment, making it even more challenging to target the cancer cells.

One other hurdle that in solid tumors, there is not a single antigen that is expressed in all the cancer cells uniformly and strongly. These are some of the hurdles that our investigators are focusing to overcome.

TARGETED ONCOLOGY: What are the next steps for incorporating CAR T-cell therapy into the solid tumor space?

Adusumilli: There are several developments in the CAR T cell engineering [process] itself, modifying the costimulatory domains and making them armored CARs to overcome the immunosuppression in solid tumors. That is one aspect that investigators are already focusing. Second, as I mentioned, is delivery. Regional delivery, at least in our example, is working well. The third is combination with checkpoint blockade immunotherapy. For example, in our trials, following single dose of intrapleural CAR T cells, we give anti-PD-L1 checkpoint blockade to enhance the functional persistence of CAR T cells. This also boosted immune responses, resulting in anti-tumor efficacy. These are some of the approaches investigators are focusing on now.

TARGETED ONCOLOGY: What are the key points you hope oncologists take away from this?

Adusumilli: I think it's in the early-stage developmental phase but understanding the tumor immune microenvironment in solid tumors is helping us [learn] how to modulate CAR engineering as well as delivery and promoting their functional persistence. We are already doing phase 1 and phase 2 clinical trials, and hopefully, we will see some results in the near future.

TARGETED ONCOLOGY: Do you see CAR T cells having an impact in the solid tumor treatment landscape?

Adusumilli: I think so. I think it's not just the CAR T cells but what we are learning from the checkpoint blockade immunotherapy, the immune mechanisms, the immune microenvironment in the tumors, and the immune resistance mechanisms. With the combination of these, I'm optimistic in the next 5 years that we will see cell therapy, especially CAR T-cell therapy, playing an important role in solid tumor treatments.

The main message is choosing the correct antigen and designing a CAR specific to the solid tumor and the delivery for each solid tumor can be different. Most importantly, doing correlative science to be able to understand what are the changes that are happening in the tumor immune microenvironment [is important] so that we can develop next-generation CAR T cells.

The field is developing rapidly, and there is an understanding from the hematological malignancies. I think combination immunotherapy is going to play a good role in the treatment going forward.