Steven ROSENBERG, et al.
T-Cell Therapy

New approach to immunotherapy leads to complete response in breast cancer patient unresponsive to other treatments

A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was unresponsive to all other treatments. This patient received the treatment in a clinical trial led by Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI’s Center for Cancer Research (CCR), and the findings were published June 4, 2018 in Nature Medicine. NCI is part of the National Institutes of Health.

“We’ve developed a high-throughput method to identify mutations present in a cancer that are recognized by the immune system,” Dr. Rosenberg said. “This research is experimental right now. But because this new approach to immunotherapy is dependent on mutations, not on cancer type, it is in a sense a blueprint we can use for the treatment of many types of cancer.”

The new immunotherapy approach is a modified form of adoptive cell transfer (ACT). ACT has been effective in treating melanoma, which has high levels of somatic, or acquired, mutations. However, it has been less effective with some common epithelial cancers, or cancers that start in the lining of organs, that have lower levels of mutations, such as stomach, esophageal, ovarian, and breast cancers.

In an ongoing phase 2 clinical trial, the investigators are developing a form of ACT that uses tumor-infiltrating lymphocytes (TILs) that specifically target tumor cell mutations to see if they can shrink tumors in patients with these common epithelial cancers. As with other forms of ACT, the selected TILs are grown to large numbers in the laboratory and are then infused back into the patient (who has in the meantime undergone treatment to deplete remaining lymphocytes) to create a stronger immune response against the tumor.

A patient with metastatic breast cancer came to the trial after receiving multiple treatments, including several chemotherapy and hormonal treatments, that had not stopped her cancer from progressing. To treat her, the researchers sequenced DNA and RNA from one of her tumors, as well as normal tissue to see which mutations were unique to her cancer, and identified 62 different mutations in her tumor cells.

The researchers then tested different TILs from the patient to find those that recognized one or more of these mutated proteins. TILs recognized four of the mutant proteins, and the TILs then were expanded and infused back into the patient. She was also given the checkpoint inhibitor pembrolizumab to prevent the possible inactivation of the infused T cells by factors in the tumor microenvironment. After the treatment, all of this patient’s cancer disappeared and has not returned more than 22 months later.   

“This is an illustrative case report that highlights, once again, the power of immunotherapy,” said Tom Misteli, Ph.D., director of CCR at NCI. “If confirmed in a larger study, it promises to further extend the reach of this T-cell therapy to a broader spectrum of cancers.”

Investigators have seen similar results using mutation-targeted TIL treatment for patients in the same trial with other epithelial cancers, including liver cancer and colorectal cancer. Dr. Rosenberg explained that results like this in patients with solid epithelial tumors are important because ACT has not been as successful with these kinds of cancers as with other types that have more mutations.

He said the “big picture” here is this kind of treatment is not cancer-type specific. “All cancers have mutations, and that’s what we’re attacking with this immunotherapy,” he said. “It is ironic that the very mutations that cause the cancer may prove to be the best targets to treat the cancer.”

The research team includes Nikolaos Zacharakis, Ph.D.; Steven A. Feldman, Ph.D.; and Stephanie L. Goff, M.D.

For more on the clinical trial, see:



Remarkable' therapy beats terminal breast cancer
by James Gallagher

The life of a woman with terminal breast cancer has been saved by a pioneering new therapy, say US researchers.

It involved pumping 90 billion cancer-killing immune cells into her body.

Judy Perkins had been given three months to live, but two years later there is no sign of cancer in her body.

The team at the US National Cancer Institute says the therapy is still experimental, but could transform the treatment of all cancer.

Judy - who lives in Florida - had spreading, advanced breast cancer that could not be treated with conventional therapy.

She had tennis ball-sized tumours in her liver and secondary cancers throughout her body.

She told the BBC: "About a week after [the therapy] I started to feel something, I had a tumour in my chest that I could feel shrinking.

"It took another week or two for it to completely go away."

She remembers her first scan after the procedure when the medical staff "were all very excited and jumping around".

It was then she was told that she was likely to be cured.

Now she's filling her life with backpacking and sea kayaking and has just taken five weeks circumnavigating Florida.

Living therapy

The technology is a "living drug" made from a patient's own cells at one of the world's leading centres of cancer research.

Dr Steven Rosenberg, chief of surgery at the National Cancer Institute, told the BBC: "We're talking about the most highly personalised treatment imaginable."

It remains experimental and still requires considerably more testing before it can be used more widely, but this is how it works: it starts by getting to know the enemy.

A patient's tumour is genetically analysed to identify the rare changes that might make the cancer visible to the immune system.

Out of the 62 genetic abnormalities in this patient, only four were potential lines of attack.

Next researchers go hunting. A patient's immune system will already be attacking the tumour, it's just losing the fight between white blood cells and cancer.

The scientists screen the patient's white blood cells and extract those capable of attacking the cancer.

These are then grown in huge quantities in the laboratory.

Around 90 billion were injected back into the 49-year-old patient, alongside drugs to take the brakes off the immune system.

'Paradigm shift'

These are the results from a single patient and much larger trials will be needed to confirm the findings.

The challenge so far in cancer immunotherapy is it tends to work spectacularly for some patients, but the majority do not benefit.

Dr Rosenberg added: "This is highly experimental and we're just learning how to do this, but potentially it is applicable to any cancer.

"At lot of works needs to be done, but the potential exists for a paradigm shift in cancer therapy - a unique drug for every cancer patient - it is very different to any other kind of treatment."

The details were published in journal Nature Medicine.

Commenting on the findings, Dr Simon Vincent, director of research at Breast Cancer Now, said the research was "world class".

He told the BBC: "We think this is a remarkable result.

"It's the first opportunity to see this sort of immunotherapy in the most common sort of breast cancer at the moment it has only been tested in one patient,

"There's a huge amount of work that needs to be done, but potentially it could open up a whole new area of therapy for a large number of people."

Nature Medicinevolume 24, pages724–730 (2018) |

Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer
N. Zacharakis, et al.


Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1,2,3,4,5,6,7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8,9,10,11. 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—SLC3A2, KIAA0368, CADPS2 and CTSB. 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 for >22 months, and it represents a new immunotherapy approach for the treatment of these patients.



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Disclosed are methods of isolating T cells and TCRs having antigenic specificity for a mutated amino acid sequence encoded by a cancer-specific mutation. Also disclosed are related methods of preparing a population of cells, populations of cells, TCRs, pharmaceutical compositions, and methods of treating or preventing cancer.


[0003] Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) or cells that have been genetically engineered to express an anti-cancer antigen T cell receptor (TCR) can produce positive clinical responses in some cancer patients. Nevertheless, obstacles to the successful use of ACT for the widespread treatment of cancer and other diseases remain. For example, T cells and TCRs that specifically recognize cancer antigens may be difficult to identify and/or isolate from a patient. Accordingly, there is a need for improved methods of obtaining cancer-reactive T cells and TCRs.


[0004] An embodiment of the invention provides a method of isolating T cells having antigenic specificity for a mutated amino acid sequence encoded by a cancer-specific mutation, the method comprising obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood from a patient; selecting T cells that express programmed cell death 1 (PD-1) from the bulk population; separating the T cells that express PD-1 from cells that do not express PD-1 to obtain a T cell population enriched for T cells that express PD-1; identifying one or more genes in the nucleic acid of a cancer cell of the patient, each gene containing a cancer-specific mutation that encodes a mutated amino acid sequence; inducing autologous antigen presenting cells (APCs) of the patient to present the mutated amino acid sequence; co-culturing T cells from the population enriched for T cells that express PD-1 with the autologous APCs that present the mutated amino acid sequence; and selecting the T cells that (a) were co-cultured with the autologous APCs that present the mutated amino acid sequence and (b) have antigenic specificity for the mutated amino acid sequence presented in the context of a major histocompatability complex (MHC) molecule expressed by the patient.


[ PDF ]
Methods of obtaining a cell population enriched for tumor-reactive T cells, the method comprising: (a) obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood; (b) specifically selecting CD8+ T cells that also express PD-1 and/or TIM-3 from the bulk population; and (c) separating the cells selected in (b) from unselected cells to obtain a cell population enriched for tumor-reactive T cells are disclosed. Related methods of administering a cell population enriched for tumor-reactive T cells to a mammal, methods of obtaining a pharmaceutical composition comprising a cell population enriched for tumor-reactive T cells, and isolated or purified cell populations are also disclosed.

[ PDF ]
Methods of producing a population of genetically modified cells using viral or non-viral vectors. Disclosed are also modified viruses for producing a population of genetically modified cells and/or for the treatment of cancer.

[ PDF ]
Methods of producing a population of genetically modified cells using viral or non-viral vectors. Disclosed are also modified viruses for producing a population of genetically modified cells and/or for the treatment of cancer.

[ PDF ]
Provided herein are methods for delaying or inhibiting T cell maturation or differentiation in vitro for a T cell therapy, comprising contacting one or more T cells from a subject in need of a T cell therapy with an AKT inhibitor and at least one of exogenous Interleukin-7 (IL-7) and exogenous Interleukin-15 (IL-15), wherein the resulting T cells exhibit delayed maturation or differentiation. In some embodiments, the method further comprises administering the one or more T cells to a subject in need of a T cell therapy.

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