Road to a Cure - use of immunotherapy

November 8, 2021 Our MBClife

This week the Road to a Cure investigators are visiting Dr Stephanie Goff in her new office at the NIH in Bethesda, Maryland. Dr Goff is a surgical oncologist and a senior member of a pioneering cancer research team led by Steven A. Rosenberg, M.D., Ph.D., Chief or Surgery at the National Caner Institute (NCI) and a man widely regarded as the father of immunotherapy. Our senior producer Victoria Goldberg is not alone on this trip. She is accompanied by a friend, who knows this place intimately. Her name is Judy Perkins. In the summer of 2015 Judy was given months to live after all treatments for her MBC had failed. She has very likely been cured by a revolutionary immunotherapy treatment, known as adoptive cell therapy, that was successfully administered by Dr Goff and her colleagues at the National Institutes of Health.

The publication of a June 2018 issue of Nature Medicine, a respected peer-reviewed medical journal may have marked, to paraphrase Winston Churchill, “not the beginning of the end, but perhaps, the end of the beginning” on the path to eradicate some forms of metastatic breast cancer.

The issue contained an article with an incomprehensible title for a lay person “Immune Recognition of Somatic Mutations Leading to Complete Durable Regression in Metastatic Breast Cancer.”

The words at the very beginning of the article shook the world on that early summer day of June 4th, 2018.

, “We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing, and it represents a new immunotherapy approach for the treatment of these patients.”

The “we” in the article is a team of researchers from the NCI led by Dr. Steven Rosenberg, Chief of Surgery at the National Cancer Institute in Bethesda and a man who is widely considered the “father of immunotherapy” A new immunotherapy approach in the article is generally known as “cellular therapy” and more specifically “adoptive cell therapy”, a method that essentially farms T cells, grows out the ones effective against cancer, and transfers them back to the patient.

A “patient” in the article was a forty-nine-year-old Florida woman with stage 4 breast cancer and large tumors throughout her body. Her name is Judy Perkins and she is alive and well today and continues to be “no evidence of disease” Our series would be incomplete without a conversation with Dr. Stephanie Goff, a senior member of Dr Rosenberg’s team and Judy’s doctor who has probably saved her life. We are very fortunate that Judy joins us as well to speak with her doctor and recall her incredible story of being part of this ground-breaking trial.

Join us as we make over 10 stops all over the U.S. (with one stop in Europe) on this Road to a Cure - every Monday until the start of the San Antonio Breast Cancer Symposium in December!

2020 Staff Clinician of the Year

Dr. Stephanie Goff, Surgery Branch, National Cancer Institute

Excerpt from nomination submission:

"Dr. Goff is a vital member of the NCI's Surgery Branch, and her exceptional organizational skills and clinical acumen facilitate the smooth operation of a scientifically innovative and technically complex approach to the protocol-driven care of patients. … Dr. Goff plays a key role as the operational nexus of the clinic, the laboratory, and production facilities. She serves as the clinical link at critical decision points: monitoring the status of the patients in the pipeline, providing input to ensure optimal management of scientific resources, and forecasting reasonable timelines to enable patients, their families, and their home oncologists to make ongoing care decisions. … It is impossible to overemphasize Dr. Goff's commitment to clinical excellence. … She is the recipient of a CCR Director's Award and an NCI Director's Award for Clinical Science. She is a trusted voice in immuno-oncology, serving as subject expert on committees for ASCO, SITC, and the DOD Breast Cancer Research Program."

Immunotherapy Explained

Cancer causes unrestrained cellular proliferation and growth, and in some cases, cancer cells can hide from or compromise the body’s immune system, which is designed to fight off infections and illnesses. This is one of many reasons why cancer is such a devastating and dangerous disease.

One of the rising treatment methods for cancer, however, is immunotherapy, a type of biological therapy. It is used to restore the immune system or greatly boost its normal functionality. Immunotherapy can introduce new elements to the body’s immune system or stimulate what is already there to help the immune system better destroy cancer cells. It can slow and stop the growth and spread of cancer, as well as effectively deliver radiation or chemotherapy to the cancer cells directly.

The classes of cancer immunotherapies described below are among the ones that might help accomplish the goal of curing cancer

What can be helpful to keep in mind is that what most (not all) immunotherapies have in common is the T ell. IL-2 grows and energizes them, adoptive T cell therapy grows and farms them, checkpoint inhibitors unleash them, vaccines inform and activate them, and CAR-T is them, the robocop version.

Immune response is complex. But in terms of cancer treatment, the goal is simple: get cancer-killing cells to do their job as quickly and selectively as possible. Anything that accomplishes that is an immunotherapy.

We are living in the checkpoint inhibitor phase of cancer immunology, or perhaps the second half of that phase (CTLA-4 was the pioneer, PD-1 / PD-L1 is the present), and already researchers speculate that we’ve plucked the low hanging fruit. There are more potential checkpoints being discovered, as well as numerous new therapeutic approaches to induce tumors that are not very immunogenic (visible to the immune system), to express unique antigens, or in some other way make those cancers viable immune system targets. Anything that makes cancer more visible as an immune target is a potential partner for drugs that unleash immune cells to attack those targets.

Cellular Therapies

A “cellular therapy” is any cancer treatment that uses a whole living cell as the “drug” (rather than just a folded protein or other molecule as the therapeutic agent).

Adoptive cell therapy, a method that essentially farms T cells, grows out the ones effective against cancer, and transfers them back to the patient. Notable advances to this method were led early on by pioneering work from Fred Hutchinson Cancer Research Center’s Phil Greenberg as well as work by Dr. Steven Rosenberg’s colleagues at the National Cancer Institute, which was one of the first centers to push this technique into the clinic and which has continued to grind out progress in this approach for decades.

CAR-T is (at present) the best-known cellular therapy and one of the most exciting to watch. It works. It’s shown to be hugely effective against those cancers the CAR can be reengineered to target. Right now that’s a limited subset of cancers, mostly blood-borne cancers. Various new approaches currently under way attempt to make that list of applicable cancers bigger, expanding the settings in which patients may safely receive this treatment while shrinking the price tag for what is now an entirely bespoke drug. Advances in gene editing and insertion are leading to numerous new groups pursuing their own CARs across the world (especially in China). It is now possible to insert several genes at a time into a T cell, which may lead to CARs with multiple protein targets. Ongoing research suggests it may also be possible to edit the T cell so that it has built-in defenses against the tumor microenvironment. CAR-T is also being tested in combination with checkpoint inhibitors and other immunotherapies.

Hot/Cold Tumors

Immunologists now categorize the interaction between an individual’s immune system and their specific tumor into three broad classes: “hot, cold, or lukewarm.” The categories are useful in describing how different tumor types, and different immune systems, present a range of dynamics which need to be addressed by different drugs or drug combinations.

“Hot” tumors are the ones most recognized by the T cells. Under the microscope you can see them massed at the tumor, and infiltrating inside the tumor (“tumor-infiltrating leukocytes”). They’re there, and yet the T cells fail to complete the job and attack and kill the tumor. Also, these hot tumors may have various ways of “exhausting” T cells so that they cannot be “reactivated.” (Remember that the immune system has a series of safeties and circuit breaker–like or timer-like elements to prevent every immune response from snowballing into a full autoimmune nightmare; even effective vaccines require a “booster shot” to reactivate T cell response.) As a result, they are present but too spent to attack. Many of these tumors tend to arise in parts of the body that are most exposed to stuff that causes cancer, like sunlight, smoke, or other carcinogens. They include skin cancers (melanoma), lung cancers (small-cell and non-small-cell carcinoma), and cancers arising in organs that deal with concentrated levels of the stuff that goes into our bodies, such as bladder, kidney, and colorectal. For DNA in the process of replicating itself, these carcinogens are like a constant bombardment. It would be like trying to write out a recipe while being pelted with golf balls; the odds are pretty good that you’ll make plenty of mistakes. In cells, these mistakes are mutations, and as you’d expect, the cancers that arise in these carcinogen-exposed organs are characterized by the highest number of “mistakes” in their DNA, and have some of the highest levels of mutations. Mutations (for these or other genetic reasons) make them highly visible to the immune system, which make them “hot.” The fact that they’re seen but not killed by the immune system means that something else is also happening, a trick that lets them survive despite being mutational peacocks. In some cases, tumor expression of PD-L1 is one of those tricks, and as such, these tumors are the most likely to be expressing PD-L1, the secret handshake telling the immune system to pay no attention, despite all the antigens. As such they’re also the tumor types most responsive to checkpoint inhibitors (anti-PD-1 or anti-PD-L1). Right now, these are the “lucky” tumor types, most likely to respond to the available immunotherapeutic drugs—and when they do respond, the responses can be profound. It’s these tumors types that have oncologists willing to use the word cure.

An entirely different problem exists if the tumor is “cold.” The immune system almost entirely fails to respond to these tumors. Under the microscope, you may believe that we have no immune system at all, which is why cold tumors are sometimes described as “immune deserts.” These tumors are, for various reasons, less or not at all visible to T cells. Unlike their hot cousins, many—but not all—cold tumors are not highly mutated, and are not highly antigenic, meaning they don’t present themselves as obvious to the immune system by presenting antigens that are clearly foreign. In this case, immune therapies that “warm” the tumor up and make it more visible (more antigenic) might be employed (such as targeting the tumor with a virus to mark it with more obviously foreign antigens). Cold tumors may also employ other tricks that prevent T cells from effectively recognizing them. Those may be aspects of the tumor microenvironment—the little world created by the tumor itself—where molecules (in various ways) disable or suppress the full immune response (which is also referred to as a “suppressive TME”). The majority of a tumor mass is not cancer, but components of the tumor microenvironment. And it’s a tough neighborhood for a T cell to infiltrate. Nature is conservative in that it doesn’t tend to evolve complexity when simplicity is successful. To generalize, that’s the reason most cold tumors don’t respond to checkpoint inhibitors: They’re the least likely sort of tumors to need a secret handshake like PD-L1 in order to survive and succeed. Their low mutation profile already makes them less visible to the immune system. With no checkpoint being taken advantage of by the tumor, inhibiting it will not change the situation. And so as you’d expect, cold tumors respond poorly to the existing checkpoint inhibitors alone, and several types don’t respond at all. To imagine why, it’s useful to think of these tumors in terms of evolution. If a mutated cell is obvious to the immune system, the immune system sees it and kills it. The more mutated, the more obvious it is, and the less likely it is to survive and grow and become what we’d call cancer—unless it has also evolved a trick to compensate for its visibility. PD-L1 is one such trick. Cold tumors simply don’t need such a trick.

A third tumor type is generally, if not helpfully, called “lukewarm.” These tumors are seen by the immune system, the T cell army masses. But then, for some reason, the attack never happens. The T cells don’t infiltrate, they don’t destroy the tumor. Immunologists sometimes compare this to an army that has heard the battle call, massed at the castle, but cannot cross the moat. This category covers a wide variety of cancers and mutation types, and it would be incorrect to typify these cancers by any single factor. Unlike their description, it’s not simply that these tumors successfully evade immune attack due to some averaging or combination of hot and cold attributes—though aspects of both may be true. It’s most accurate to think of these tumors as having a unique profile of immune defense that allows them to survive and thrive without being totally invisible to the immune system. These tumors include some—but not all—glandular tumors. What matters is less often where these cancers arise than what typifies them. In some cases, what makes them “lukewarm” is that despite being obvious, they exist in places that are difficult for immune cells to infiltrate. They may be typified by tumors with a tough outer layer that repels infiltrators. They may have evolved an almost fantastical outer line of defense. But generally, they are typified by a moderate expression of PD-L1, a moderate mutational load, a moderate antigen presentation, and often an immune-suppressive microenvironment that turns down immune response in the T cells at the gates. And there are some single therapies being tested to uniquely address these tumor types, but it’s fair to say that various elements of hot and cold tumor approaches—including checkpoint inhibitors, therapies to warm the tumor by making it more immunogenic, and approaches to counteract suppressive elements in the tumor microenvironment—may all be considered in changing the situation to one where they are recognized, targeted, infiltrated, and destroyed by the immune system. Here too, various stages of the cancer immunity cycle are being targeted to get those T cells across the moat (to become tumor-infiltrating leukocytes), activated, and recharged. Nine: It’s Time 1. The footage is also now incorporated in the official music video of that Imagine Dragons song. See Jesse Robinson, “Imagine Dragons—for Tyler Robinson,” YouTube, October 27, 2011, https://www.youtube.com/

Graeber, Charles. The Breakthrough (Immunotherapy and the Race to Cure Cancer) (p. 227). Grand Central Publishing.

The Tumor Microenvironment or Stroma

From the transcript of the episode

I would say an understanding of what tumor stroma is requires you to understand that when we take out a tumor, every single cell that's in that mass that we take out is NOT a cancer cell. Quite frequently, very few of them are.

And so you have to (our pathologist can help us) look and see which parts of that mass that we take out are actually tumor cells , which parts are the immune system infiltrating that mass, which parts are the connective tissue that we have all over our body(pieces of collagen pieces of connective tissue).

It all combines to make this mass. It is very rare, that you take out a tumor from somebody and it's 100% cancer. There's almost always some other kind of tissue cell in there. And so anything that's not a cancer is considered part of the tumor micro environment or stroma and some tumors, , pancreas in particular has a very dense stroma, such that if you were to take out a tumor that's three centimeter sphere, there may only be a centimeter or so that's actually tumor and the rest may be inflammatory tissue around it.

And that's what we call stroma.

Mentioned in this Episode

Immunotherapy

Nikolaos Zacharakis et al., “Immune Recognition of Somatic Mutations Leading to Complete Durable Regression in Metastatic Breast Cancer,” Nature Medicine, 2018, 24:724–730.
James N. Kochenderfer et al., “Eradication of B-Lineage Cells and Regression of Lymphoma in a Patient Treated with Autologous T Cells Genetically Engineered to Recognize CD19,” Blood, 2010, 116:4099–4102, doi:10.1182/blood-2010-04-281931. 21.
James N. Kochenderfer et al., “B-Cell Depletion and Remissions of Malignancy along with Cytokine-Associated Toxicity in a Clinical Trial of Anti-CD19 Chimeric-Antigen-Receptor-Transduced T cells,” Blood 119, no. 12 (2012): 2709–20.

Judy Perkins

See this content in the original post

Our MBC Life

Road to a Cure - use of immunotherapy

Immunotherapy Explained

Further Reading

Mentioned in this Episode