Improving Outcomes for Cancer patients via Immunotherapy

Dr AV Malini is the lead of Clinical Translational Technologies and Operations at Biocon Bristol-Myers Squibb Research Center (BBRC)

malini-photograph

We are seeing revolutionary changes in our understanding of cancer, the foremost fact being that our
own immune system can identify and destroy tumor cells. This has led to unprecedented advances in
treatment modalities, especially in the form of immunotherapy and combination regimens to treat
molecularly defined subset of patients. In this context, the detailed analysis of the immune
microenvironment in primary tissue biopsy samples by a pathologist is essential to stratify and personalize therapy to individual patients and tumor types.

According to the immunoediting hypothesis characterized by the 3 E's, the host immune response first
tries to Eliminate the tumor cells, failing which it attains a dynamic Equilibrium with the tumor and
ultimately loses the fight when the tumor manages to escape by selective pressure mechanisms. The
presence of leukocytes within human tumors was described by Rudolf Virchow, in 1863. Although this
was thought to play a protumorogenic role, several studies have now revealed that the presence of
inflammatory cells within tumors can confer a favorable prognosis. Tumor infiltrating lymphocytes (TILs),
tumor associated macrophages (TAM), dendritic cells, myeloid derived suppressor cells and natural killer
are some of the key types of leukocytes that form part of this milieu. The location (intra-tumoral, stromal, invasive margin) and type of immune cells (TILs, macrophages, dendritic cells) within a tumor can provide important insights on disease progression and prognosis thus serving as potential biomarkers. As examples, it is now well known that patients with tumors (like melanomas, colorectal carcinomas (CRC), urothelial, ovarian, gastroesophageal, breast, prostate, pancreas, and cervix carcinomas) rich in TILs at their invasive margins have better survival rates than those that lack them. The CD3 / CD8 based immunoscore assessment in colorectal carcinomas has been shown to be superior to the TNM staging in the case of CRC. With TAM, the functional subsets are known to play different roles; while the M1 subset is said to be immunostimulatory, the M2 subset is said to be immunosuppressive.

Till recently Immunotherapy for cancers has been known in the form of intravesicular BCG use for the
treatment of bladder tumors and anti-cancer vaccines. Bristol-Myers Squibb, in 2011, transformed the
approach by using therapeutic antibodies like the anti CTLA4 inhibitor Ipilimumab that targets specific
coinhibitory receptors on T cells that enhance the effector T cell function by converting exhausted T cells
into active T cells to promote antitumor immunity. Co-inhibitory- receptors like CTLA- 4 (cytotoxic Tlymphocyte- associated protein 4), PD-1 (programmed cell death protein 1), and LAG-3 (lymphocyte
activation protein 3), suppress T cell activation, and costimulatory receptors such as CD28, ICOS, and
CD40L promote T cell activation following the engagement of a T cell receptor with an antigenic peptide
presented in the context of Major Histocompatibility Complex. While the anti-PD1 antibody is already in
the clinic, there are several novel therapeutics against other immune checkpoints that are currently in
clinical development. Although therapeutic antibodies against CTLA4 and PD1 have revolutionized the way we treat cancer, there is a lot yet to be understood. Even with companion diagnostics testing (as with anti-PD1 therapy) it is seen that not all patients derive equal benefit. Tumors have not studied textbooks on pathology! Different tumor types are seen to respond differently as is the case with treatment-naïve versus relapsed or recurred tumors. By integrating traditional histopathology and emerging techniques in digital pathology along with genetic and genomic assessment of both pretreatment and post treatment biopsies we are beginning to understand the tumor and its surrounding environment (both stromal and immune cell) at a single cell level and thus helping us to move one more step further towards better patient stratification, a pre-requisite today for improving patient outcomes.

In order to make the Science work, we must also acknowledge that the primary source for any form of
reliable data starts with the biological sample. The challenges related to access to well-annotated clinical
samples, their storage and processing are many and need to be addressed through collaborative efforts
between all stakeholders, i.e., greater interactions between clinicians and basic science researchers as
well as between academia and industry.

As Immunotherapy becomes part of the standard of care in clinical oncology, the field of Pathology thus
truly finds itself at the centre of personalized predictive medicine.

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