The tipping point

March 7, 2020 0 By S Harachand

From the year 2016 to 2017, the US recorded the biggest decline in cancer deaths. At 2.2%, the drop in mortality rates from cancer is considered the largest-ever single-year decline in the past 26 years.

With this, death rates from cancer have fallen by 29% from 1991 to 2017, according to data released by the American Cancer Society. The decline in deaths from lung cancer drove the record drop, found the annual statistics report by ACS.

Apart from lung cancer; colorectal, breast and prostate cancers also showed lower cancer mortality.

The decade that has just gone by has been one of the most transformative as far as cancer care is concerned.

Today, it is clear that the avoidance of tobacco and public health measures like immunisation against cancer-causing infections and other healthy lifestyle choices can prevent between 30-50% of cancers. 

The link between tobacco use and several cancers is well established. The rates of new lung cancer cases dropped by 5% per year in men and 4% per year in women from 2013 to 2017. Lung cancer death rates declined by 51% from 1990 to 2017 among men and 26% from 2002 to 2017 among women. The differences reflect historical patterns in tobacco use, where women began smoking in large numbers many years later than men and were slower to quit, says the ACS report.

The smoking patterns, however, do not appear to explain the higher lung cancer rates being reported in women compared with men born around the 1960s.

Breast cancer death rates declined 40% from 1989 to 2017 among women. Prostate cancer death rates are down by 52% from 1993 to 2017 among men.

Colorectal cancer death rates fell 53% from 1980 to 2017 among men and by 57% from 1969 to 2017 among women.

The accelerated drops in cancer mortality are likely due, at least in part to, advances in cancer treatment over the past decade.

Unleashing the power of immune system

The discovery that unleashing the power of the immune system is a smart way to fight cancer has revolutionised cancer treatment.

The immune system can adapt continuously and dynamically. The system’s “memory” allows it to target and eliminate cancer if a tumour manages to escape detection.

Immunotherapy can teach the immune system to recognise and launch an attack against specific cancer cells.

Approved by the world’s leading drug regulators for a variety of cancers, immunotherapy has changed the therapeutic paradigm in an increasing number of cancers.

Molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD-1 essentially act as the “brakes” or the natural regulatory mechanism of the immune system. Checkpoint inhibitors target exactly these immune checkpoints. They usually engage when proteins on the surface of T cells recognize and bind to partner proteins on other cells, including some tumour cells. When checkpoint and partner proteins bind together, they send an “off” signal to T cells, rendering the immune system incapable of destroying cancer.

“Checkpoint inhibitors are antibody drugs designed to block or neutralise brakes and get the immune system work,” says Vishva M Dixit, Vice President at Physiological Chemistry at Genentech, CA.

Already, the potential of checkpoint immunotherapy has been validated in melanoma and lung cancer, he adds. 

The first checkpoint inhibitor, ipilimumab, a CTLA-4 targeting antibody drug to treat melanoma, was approved by the USFDA in 2011.

Currently, several such biological drugs are available, such as pembrolizumab, nivolumab, durvalumab, avelumab and cemiplimab, which target the other checkpoint, PD-1 or its partner protein PD-L1. Some tumours turn down the T cell response by producing lots of PD-L1. 

Immune checkpoint inhibitors have already been approved for a wide range of cancers and solid tumours caused by errors in DNA that occur when the DNA is copied. 

“Currently, certain immune checkpoint inhibitors are approved for first-line treatment of certain cases of melanoma, lung cancer, and renal cell carcinoma, among others. It will be interesting to see how further approvals of immunotherapies as earlier lines of treatment will change the landscape of cancer treatment,” says the American Association for Cancer Research (AACR), the world’s first and largest cancer research organization.

Immunotherapy, however, doesn’t always work for every patient, and inevitably, checkpoint blockage comes with ample scope for potential toxicities. Since these antibody drugs alter the checkpoint inhibition, they can lead to inflammation of organ systems.  

Proponents of immunotherapy, however, argue that drugs like anti-PD-1 agents and anti-CTLA4 therapies should not be discounted because of their toxicities. Immunotherapeutic agents should be offered to patients who are eligible to receive them, given their efficacy and despite their side effects.

At least in melanoma, they add, it is really important that people receive anti-PD-1 or anti-PD-L1 and anti-CTLA4 treatment in the front-line setting if eligible.

People shouldn’t be afraid of the toxicity of these agents. Even if they are toxic, researchers are going to have to learn how to manage them because these are very effective agents in almost every cancer. It’s now a part of the armamentarium of oncologists. In the long run, they predict that immune checkpoint inhibitors and immunotherapies will be the most common agent that oncologists prescribe in their practice. 

“We need these drugs to work for more people,” said James P. Allison of The University of Texas MD Anderson Cancer Center, while receiving the 2018 Nobel prize for medicine, which he shared with Tasuku Honjo of Kyoto University in Japan, for their work in basic research that led to the approval of the first checkpoint inhibitor drug by the US FDA in 2011.

Incredible results with ‘living drugs’

Other than checkpoint blockers, the major types of immunotherapy employed against cancer include targeted antibodies, cancer vaccines, adoptive cell transfer, tumour-infecting viruses, cytokines and adjuvants.

CAR T-cell therapy came to the limelight with the big-bang approvals of tisagenlecleucel (Kymriah) to treat relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (ALL) and axicabtagene ciloleucel (Yescarta) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) by the US FDA. Both the therapies target the CD19 antigen, which is found in many types of B-cell cancers.

CAR T-cell therapy is sometimes described as a `living drug’, because it is made out of T-cells – the primary workhorse of the immune system. The making of the therapy involves drawing blood from patients and the genetic engineering of the T cells by an inactivated virus to produce chimeric antigen receptors on the surface. These synthetic molecules allow T cells to recognise and attach to a specific protein, or antigen, on tumour cells. Then they are “expanded” in the laboratory into the hundreds of millions. The engineered cells further multiply in the patient’s body, and have the ability to recognise and kill cancer cells that harbour the antigen on their surfaces.

Tisagenlecleucel and axicabtagene ciloleucel therapy showed initial remission rates as high as 90% in B-cell blood cancers. However, the emergence of cancer cells that do not express CD19 following treatment to evade the engineered CAR T-cell brought down long-term survival rates to significantly lower rates. Efforts are now focused on overcoming the CD19 downregulation of CAR T-cells therapy.

CD19-targeted CAR T cells have produced complete responses to the treatment in more than half of the patients with advanced diffuse large B-cell lymphoma.

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential, say experts.

A large number of clinical studies are now underway to explore the potential of CART-cells in various malignancies as well, other than blood cancers.

Safety is another concern haunting this breakthrough cancer therapy. CAR T-cells have been shown to cause cytokine release syndrome (CRS). 

B-cell aplasia, where B cells die off massively, is yet another potential side effect of CAR T-cell therapy. More recently, cerebral oedema has also been seen in some of the larger trials.

Tumour-infiltrating lymphocytes (TIL) are also employed in adoptive cell therapy.

TIL therapy aims to eliminate cancer cells by infusing a large number of manipulated lymphocytes to kill or to overcome the signals that the tumour is releasing to suppress the immune system.

TILs have been successfully used by NCI researchers to treat patients with advanced melanoma and several other cancers, including cervical cancer. More recently, they have found that TILs that recognize cancer cells with mutations specific to colorectal and liver cancer led to regression.

TIL therapy can cause capillary leak syndrome, resulting in dangerously low blood pressure. 

Precision medicine: The way forward

Unlike standard chemotherapy that act on all rapidly dividing normal and cancerous cells, drugs targeting specific molecules associated with cancer are currently the focus of much of anticancer drug development.

Therapies targeted at interfering with human epidermal growth factor receptor 2 protein (HER-2) have scripted a new chapter in breast cancer treatment. 

One in five women with breast cancer have HER-2 expressed at high levels on the surface of some cancer cells. Trastuzumab and pertuzumab are among the several targeted therapies directed against HER-2. Antibody-drug conjugates (ADCs) like ado-trastuzumab emtansine and fam-trastuzumab deruxtecan are advanced therapies that deliver the chemo part of the drug directly to the tumour.

Trastuzumab is considered a breakthrough in the treatment of HER2-positive metastatic breast cancer as the biological agent, in combination with chemo, increased both survival and response rates.

Another way is to target gene mutations that drive cancer progression. Vemurafenib and dabrafenib inhibit the action of BRAF, the cell growth signalling protein, which is present in an altered form known as BRAF V600E in many melanomas. As per phase 3 data, patients with metastatic melanoma showed a 53% response rate to vemurafenib compared to 7-12% with the best chemotherapeutic treatment, dacarbazine.

BRAF mutants cause cancer by excessively signalling cells to grow.

More than 30 BRAF mutations are linked to human cancers with high variation among various cancers. While the frequency of BRAF mutants is as high as 80% in melanoma, it is only 5% in colorectal cancer and 1-3% in lung cancer.

Similarly, poly ADP ribose polymerase (PARP)-inhibitors like olaparib and talazoparib help block the DNA-repairing PARP proteins in mutated BRCA1 and BRCA2 genes, leading to the death of cancer cells. These drugs can be used to treat metastatic, HER2-negative breast cancer in women with a BRCA mutation. Only a small portion of women with breast cancer, however, have a mutated BRCA gene.

About 30% to 40% of breast cancers have a mutated PIK3CA gene. Alpelisib, a targeted PI3K inhibitor, is useful in such cases.

Imatinib, which targets the BCR-ABL fusion protein, is currently the standard first-line treatment for Philadelphia-chromosome-positive patients with chronic myelogenous leukaemia (Ph+ CML). More than 90% of CML cases are caused by Ph chromosome abnormality. 

The drug is also indicated for Ph+ acute lymphocytic leukaemia (ALL) and certain types of gastrointestinal stromal tumours (GIST) and chronic eosinophilic leukaemia (CEL), among others.

Second generation BCR-ABL inhibitors such as nilotinib, dasatinib, bosutinib and ponatinib are approved for the treatment of imatinib-resistant or intolerant CML.

Blocking the supply line: Growth of solid tumours depends upon blood supply. Tumours can actually cause this blood supply to form by giving off chemical signals that stimulate angiogenesis. Tumours can also prompt nearby normal cells to produce angiogenesis signalling molecules. Angiogenesis inhibitors deprive the tumours of essential nutrients by blocking the growth of blood vessels.

Bevacizumab, that targets vascular endothelial growth factor (VEGF), has turned out to be a real wonder drug in this segment. 

Since its first approval by USFDA in 2004 for use in metastatic colon cancer in combination with standard chemotherapy, bevacizumab has been approved for use in nonsquamous non-small cell lung cancer, renal cancers, ovarian cancers, and glioblastoma multiforme, breast cancer (except in the US), cervical cancer, ovarian epithelial, fallopian tube and primary peritoneal cancers.

Axitinib, cabozantinib, everolimus, lenalidomide, lenvatinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib and vandetanib are among other approved angiogenesis inhibitors.

 Synthetic versions of sex hormones are used to treat prostate and hormone-receptor-positive breast cancers. As promoters of cell death, apoptosis-inducing factors play a contributory role in the growth and aggressiveness of certain types of colorectal, prostate and pancreatic cancers.

Researchers are working on cell signal transduction inhibitors, gene expression modulators and apoptosis inducers to tame different types of cancers more effectively.

With the help of information on a person’s tumour genes and proteins, precision medicine enables a diagnosis, helps chart out a treatment plans, find out how well the treatment is working and make a prognosis.

While we’re not quite at the point of having truly personalised medicine, the use of therapies targeting specific characteristics of a patient’s cancer is now fairly common. 

In fact, all of the 11 new therapeutics approved by the FDA in the United States last year were targeted therapies that attack cancer cells based on specific traits such as genetic mutations. These traits distinguish the cells from non-cancerous ones, points out AACR, which is home to many premier researchers in the field, including the Nobel laureate James P Allison. 

Vanquishing vaccines

Cancer cells contain tumour-associated antigens. These antigens are either not present in normal cells or are present in very low levels. Treatment vaccines can help the immune system learn to recognize and react to these antigens and destroy cancer cells that contain them.

Vaccines made out of tumour-associated antigens can cause an immune response in any patient whose cancer produces that antigen. This type of vaccine is, however, still in experimental stages.

Vaccines can be produced from a patient’s antigen-presenting dendritic cells as well. Sipuleucel-T is one such a therapeutic vaccine currently approved by USFDA to treat metastatic hormone-refractory prostate cancer. This cellular adoptive immunotherapy may help the immune system kill prostate cancer cells. 

Studies are also ongoing on vaccines derived from tumour cells. Since these vaccines are custom-made, they cause an immune response against features that are unique to one’s cancer.

In contrast to overexpressed proteins, tumours also display neoantigens, unique targets that arise as a result of mutations. Several types of neoantigen vaccines are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials.

Vaccines are preventive, in the conventional sense. Cervical cancer and head and neck cancer can be caused by the human papillomavirus, or HPV, whereas liver cancer can be caused by hepatitis B virus or HBV. Cervarix and Gardasil are currently approved to prevent HPV strains that can potentially cause anal, cervical, head and neck, penile, vulvar, and vaginal cancers. While the only FDA approved HBV vaccine (Heplisav-B) is indicated to help prevent the development of HBV-related liver cancer. 

Impact of genetics

Ongoing research in the field of precision medicine is focused on understanding which patients will benefit from immunotherapy, monitoring cancer evolution with liquid biopsy approaches and using big data sets to understand how genetics impacts treatment response. One of the challenges to utilising big genomic data sets is that it takes time and effort to aggregate and analyse how genetic alterations affect clinical outcomes.

Another challenge is determining how best to share data while aligning with regulations that govern the use of genetic data, says AACR. 

Even as immunotherapy and targeted drug approvals have expanded greatly over the past several years, most newly diagnosed cancers continue to be treated with conventional cancer therapies, such as surgery, chemotherapy and radiation therapy.

Clearly, the advent of targeted approaches did succeed in pinning down certain malignancies. But cancer is a generic term given to several different diseases of complex genetic origin with a high degree of predisposition to epigenetic factors and showing strong environmental and lifestyle interplay. It is daunting to tame a malady of such multifarious nature. Despite relentless efforts, the global epidemic of cancer remains unchallenged and continues to grow in leaps and bounds.