Immunotherapy is paying off at last

Detect, destroy, remember is the mantra of the immune system as it campaigns against infectious invaders and the body’s own abnormal cells.

For decades, researchers have strived to use the immune system to destroy cancer cells. In addition to recognising, destroying and remembering viral and bacterial infections, the immune system routinely does the same thing to the body’s own abnormal cells, the type that develop into cancer. However, vaccines and other immune therapies developed to hit cancer were bedevilled by tumour defences, resulting in minimal impact on the cancer if not outright treatment failure.

Now, immunotherapy is finally offering viable treatment options for some cancers.

Amazing results against metastatic melanoma

Dr Jim Allison, chair of Immunology at The University of Texas MD Anderson Cancer Center, has developed an entirely different way of treating cancer by targeting the immune system, not the tumour itself.

Allison’s basic science research on the biology of T cells, immune system attack cells primed to identify and destroy infections and the body’s abnormal cells, has led to several discoveries:

• Identification of the receptor on T cells used to recognise and bind to antigens - abnormalities that mark defective cells or viruses and bacteria for attack.
• The discovery that T cells require a second molecular signal from co-stimulatory molecules to launch a response after they’ve bound to an antigen.
• A discovery involving a receptor on T cells called CTLA-4 that acts as a built-in off switch to stop T cells from attacking. These immune checkpoints usually protect normal tissues from autoimmunity and aren’t effective on abnormal cells. Cancer cells, however, activate CTLA-4.

Allison then developed an antibody that led to development of ipilimumab to block CTLA-4. In clinical trials against stage 4 melanoma, the drug extinguished the disease in 24% of patients for up to 12 years and counting - unprecedented results against metastatic melanoma. The drug, now called Yervoy, was approved to treat melanoma by the US Food and Drug Administration in 2011.

Allison’s basic research on the biology of T cells - the supremely targeted shock troops of the immune system - revealed an important reason why. He found that a receptor on T cells acts as an ‘off switch’ to shut down activated T cells. Designed to protect normal cells from T cell attack, tumour cells also are equipped to fire up the receptor CTLA-4 to stop a targeted immune system assault.

Additional immune checkpoints and experimental drugs to block them are now being developed by others. Clinical trials of these agents and ipilimumab focusing on melanoma, lymphoma, lung, breast, gastric and prostate cancers are already in progress, with more to come.

Targeting cancer stem cells in brain cancers

An early-phase clinical trial of an experimental vaccine that targets cancer stem cells in patients with recurrent glioblastoma multiforme, the most common and aggressive malignant brain tumour, has been launched by researchers at Cedars-Sinai’s Department of Neurosurgery, Johnnie L. Cochran, Jr. Brain Tumour Center and Department of Neurology.

Like normal stem cells, cancer stem cells have the ability to self-renew and generate new cells, but instead of producing healthy cells, they create cancer cells. In theory, if the cancer stem cells can be destroyed, a tumour may not be able to sustain itself, but if the cancer originators are not removed or destroyed, a tumour will continue to return despite the use of existing cancer-killing therapies.

The Phase I study, which will enrol about 45 patients and last two years, evaluates safety and dosing of a vaccine created individually for each participant and designed to boost the immune system’s natural ability to protect the body against foreign invaders called antigens. The drug targets a protein, CD133, found on cancer stem cells of some brain tumours and other cancers.

Immune system cells called dendritic cells will be derived from each patient’s blood, combined with commercially prepared glioblastoma proteins and grown in the laboratory before being injected under the skin as a vaccine weekly for four weeks and then once every two months, according to Jeremy Rudnick, MD, neuro-oncologist in the Cedars-Sinai Department of Neurosurgery and Department of Neurology, the study’s principal investigator.

Dendritic cells are the immune system’s most powerful antigen-presenting cells - those responsible for helping the immune system recognise invaders. By being loaded with specific protein fragments of CD133, the dendritic cells become ‘trained’ to recognise the antigen as a target and stimulate an immune response when they come in contact.

The cancer stem cell study is the latest evolution in Cedars-Sinai’s history of dendritic cell vaccine research, which was introduced experimentally in patient trials in 1998.

Immune cell response to cervical precancer vaccine

Preliminary results of a small clinical trial show that a vaccine used to treat women with high-grade precancerous cervical lesions triggers an immune cell response within the damaged tissue itself. The Johns Hopkins scientists who conducted the trial said the finding is significant because measuring immune system responses directly in the lesions may be a more accurate way to evaluate so-called ‘therapeutic’ vaccines than by the conventional means of blood analysis.

“It’s difficult to measure immune cell responses to therapeutic vaccines, but we believe that clinical studies could tell us more about the value and function of the vaccines if we check for the response in the lesions, where the immune system is fighting precancerous cells,” says Connie Trimble, MD, associate professor of gynaecology and obstetrics, oncology and pathology at Johns Hopkins’ Kimmel Cancer Center.

Each of the 12 women in the clinical trial was diagnosed with high-grade precancerous cervical lesions linked to a strain of the human papillomavirus (HPV16) most commonly associated with cervical cancer. In a bid to treat the lesions and prevent cervical cancer, they received three vaccine injections in the upper arm over an eight-week period.

Two types of vaccines were used for the study: one constructed with genetically engineered DNA molecules that teach immune system cells to recognise premalignant cells expressing HPV16 E7 proteins and one that is a non-infectious, engineered virus that targets and kills precancerous cells marked by HPV16 and HPV18 E6 and E7 proteins.

Seven weeks after the third vaccination, the investigators surgically removed cervical lesions from all of the women. Blood samples and cervical tissue were collected from each patient at the beginning and end of the trial, letting scientists compare immune cell responses before and after vaccination.

In three of six patients treated with the highest dose of the vaccine, and one patient in each of the two groups receiving lower doses of the vaccine, the cervical lesions disappeared. The first patient was treated in 2008 and the 12th in 2012. None of the 12 patients has, so far, developed more lesions.

Among those vaccinated, the investigators found significant increases of CD8 T-cells, the ‘killer’ cells of the immune system, in cervical tissue. Blood samples failed to show as strong a pre- and post-vaccination effect. The investigators also said the vaccine did not have the unwanted consequence of altering the number of T-regulatory cells, which suppress immune system responses.

“We found striking immune system changes within cervical lesions, which were not as evident in the patients’ peripheral blood samples,” says Trimble.

The investigators also measured gene expression of post-vaccinated cervical cells in three of the patients and found increased expression of several genes (CXCR3, Tbet and IFNβ) associated with activation of the immune system. They found many similarities in T-cell receptors in the cervical tissue of two of the vaccinated patients, “suggesting that the T-cells are seeing the same thing”, says Trimble.

The Johns Hopkins team says it plans to enrol some 20 more patients, testing a combination of the vaccines and a topical cream to enhance the immune response locally.

Trimble says that the conventional practice of measuring vaccine effectiveness via blood tests probably began with mouse models used for immunotherapy research. “But the way that HPV and the immune system behave in humans may be far different,” she says.

HPV causes nearly all cervical, anal, vaginal and penile cancers and nearly two-thirds of oral cancers. In the cervix, about 20 to 25% of high-grade lesions will disappear spontaneously. Because there is no standard way to predict lesions that will disappear, the current standard of care for these lesions is surgical removal. Current preventive vaccines for HPV are not effective on women already exposed to the ubiquitous virus.