How Turning ‘Cold’ Tumors Into ‘Hot’ Ones May Improve Response to Immunotherapy

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The proliferation of immunotherapeutics in the treatment of cancer over the past decade has revolutionized the way many cancers are treated, especially lung cancer and melanoma, as well as some blood cancers, including leukemia and lymphoma, drastically improving outcomes for many patients with these diseases, even in the metastatic setting. However, for most common cancers, such as pancreatic, colorectal, and breast cancers, immunotherapy in its different forms, including checkpoint blockers, vaccines, and chimeric antigen receptor (CAR) T-cell therapies, has not been as successful, and numerous studies are underway to discover why immunotherapies work or do not work in individual patients.

Robert H. Vonderheide, MD, DPhil,

Robert H. Vonderheide, MD, DPhil,

A recent laboratory study by Robert H. Vonderheide, MD, DPhil, Director of the Abramson Cancer Center of the University of Pennsylvania, and his colleagues, including Ben Z. Stanger, MD, PhD, Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, investigating the factors underlying pancreatic tumor immune heterogeneity and immunotherapy sensitivity, is shedding light on how to enhance immunotherapy based on the molecular structure of a patient’s tumor and activate the immune system to destroy cancer cells, thereby turning immunologically “cold” tumors into “hot” ones.1 Immunologically cold tumors, explained Dr. Vonderheide, are cancers that for various reasons contain few infiltrating T cells and are not recognized and do not provoke a strong response by the immune system, making them difficult to treat with current immunotherapies. Cancers that are classically immunologically cold include glioblastomas as well as ovarian, prostate, pancreatic, and most breast cancers.

In contrast, immunologically hot tumors contain high levels of infiltrating T cells and more antigens, making them more recognizable by the immune system and more likely to trigger a strong immune response. Among the cancers considered to be immunologically hot are bladder, head and neck, kidney, melanoma, and non–small cell lung cancers. However, even within these immunologically hot cancers, only a minority of patients seem to benefit from immunotherapy. Combining immunotherapy with modified formulations of traditional cancer therapies, including radiation therapy and chemotherapy, may help stimulate an inflammatory response that jolts the immune system into action, eliciting a more effective response to treatment and more durable remissions in patients with a variety of tumor types, according to Dr. Vonderheide.

The ASCO Post talked with Dr. Vonderheide about his current research in pancreatic cancer as well as how combining checkpoint inhibitors with radiation therapy and chemotherapy may potentially turn immunologically cold tumors into hot ones and improve patient outcomes.

Helping the Immune System Recognize Cancer Cells

How are immunologically cold tumors able to exclude the immune system or hide from it altogether, keeping it from achieving an immune response and rendering immunotherapy ineffective?

Understanding whether a tumor is immunologically cold or hot is therapeutically important; we think immune checkpoint antibodies, such as anti–programmed cell death protein 1 (anti–PD-1) and anti–programmed cell death ligand 1 (anti–PD-L1), work primarily by activating T cells that have already responded to the tumor and are held in check. In immunologically hot tumors, the problem is that the cancer puts a molecular brake on the T cells; if we use checkpoint antibodies to inhibit the function of those molecules, the T cells can function again and begin to destroy the tumor. And we’ve seen this activity in many tumors, especially in melanoma and lung cancer.

“Although there are immunologically hot and cold tumors in all cancers, the majority of pancreatic tumors are immunologically cold [difficult to treat with current immunotherapies].”
— Robert H. Vonderheide, MD, DPhil

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In pancreatic cancer, checkpoint inhibitors are rarely effective unless the tumor is microsatellite instability–high, which accounts for only about 1% of all patients with the disease. We have been studying pancreatic cancer in the laboratory using mouse models to look at tumor heterogeneity and the different ways the cells grow, spread, and respond to treatment. What we’ve learned is that although there are immunologically hot and cold tumors in all cancers, the majority of pancreatic tumors are immunologically cold.

What we learned in our mouse study is that immunologically cold pancreatic tumor cells make a signaling protein called CXCL1, which recruits another type of immune cell called a myeloid cell. Myeloid cells are immunosuppressive and prevent T cells from attacking the tumor. Knocking out CXCL1 in these tumors boosted T-cell infiltration and sensitivity to immunotherapy.

However, the question of what to do about immunologically cold tumors requires a better understanding of not just the histology of these tumors, but the fundamental biology of the cancer, regardless of its type, and why there has not been a T-cell response to these tumors. Therefore, simply giving PD-1 antibodies by themselves is unlikely to result in tumor regression.

Making ‘Cold’ Tumors Visible to the Immune System

How can the response to an immunotherapy be improved and maintained in both immunologically cold and hot tumors?

We are investigating how we can combine a PD-1 inhibitor and other checkpoint inhibitors as we do in traditional cancer therapies in immunologically cold tumors to make them visible again to the immune system and to strengthen immune responses by checkpoint inhibitors in immunologically hot tumors. Studies have suggested that modified doses of radiation therapy and chemotherapy may strengthen immune responses produced by checkpoint inhibitors. For example, in lung and breast cancers, the combination of chemotherapy and immunotherapy is showing effectiveness—not just in killing the tumor cells, but in exposing those tumor cells to the immune system as well.

So, we are seeing, perhaps, proof of principle that you can combine conventional therapies with checkpoint inhibitors to make them work better and turn immunologically cold tumors into hot ones.

Using Radiation Therapy to Boost Immune Response

When radiation therapy is given to bolster an immune response, should it be given in a reduced dose compared with that used conventionally to treat cancer?

“It appears that giving standard doses of chemotherapy along with checkpoint inhibitors may be the optimal way to spur the immune T cells into action.”
— Robert H. Vonderheide, MD, DPhil

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There are two variables in radiation therapy: the amount of an individual dose and how many doses are given to treat a cancer. Conventional radiation uses low amounts of single doses of external-beam radiation that are delivered over many, many days and weeks. The amount of radiation therapy that appears the most immunogenic is a fairly high dose of external-beam radiation delivered just a few times.

Combining Chemotherapy With Immunotherapy

How does chemotherapy in conjunction with checkpoint inhibitors stimulate a potent immune response in patients with immunologically cold tumors?

The research in this area is moving forward. There was probably wariness about combining immunotherapy with chemotherapy, and there has been some hesitancy to give patients both therapies at the same time. In fact, it appears that giving standard doses of chemotherapy along with checkpoint inhibitors may be the optimal way to spur the immune T cells into action.

However, probably not every type of chemotherapy will have this effect, and we need to understand which chemotherapies cooperate with the immune system and which ones do not.

Have you launched clinical trials in patients using combinations of chemotherapy and checkpoint inhibitors?

Yes, we have a number of studies underway. The largest one is a randomized phase II study performed with the Parker Institute for Cancer Immunotherapy; it is investigating the combination of standard U.S. Food and Drug Administration–approved drugs for patients with metastatic pancreatic cancer and the anti–PD-1 monoclonal antibody nivolumab and an anti-CD40 monoclonal antibody called APX005M. In this clinical trial, one-third of patients receives chemotherapy plus nivolumab; one-third receives chemotherapy plus the anti-CD40 antibody; and one-third receives chemotherapy and both nivolumab and the anti-CD40 antibody.

We are trying to determine whether there is a survival benefit to adding any type of immune therapy to chemotherapy, and if so, which combination of therapies works best. All of these combinations have shown activity in laboratory studies.

We have also launched a randomized study in patients with metastatic melanoma investigating whether radiation therapy in combination with nivolumab and the anti–cytotoxic T-lymphocyte– associated protein 4 antibody ipilimumab adds a benefit beyond the standard of care. In this study, patients are randomly being assigned to receive radiation therapy to one of their lesions or no radiation therapy.

The biology is very clear in the laboratory. Now, we need to test these concepts in human trials and try to make headway in the treatment of patients with these common cancers, especially in the advanced-stage setting.

DISCLOSURE: Dr. Vonderheide has received consulting fees from Apexigen, AstraZeneca, Celgene, Genentech, Janssen, Lilly, MedImmune, Merck, and Verastem; and research funding from Apexigen, Fibrogen, Inovio, Janssen, and Lilly.


1. Li J, Byrne KT, Yan F, et al: Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49:178-193, 2018.