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Overview

Treating the cancer (Treatment approaches & methodologies)

Second opinion (how does it benefit you and your treatment)

A full and comprehensive diagnosis of cancer requires a pathologic investigation of tissue suspected of being cancerous and this requires biopsy of the suspicious area. Cancer may be suspected on clinical and/or radiological grounds but the diagnosis can only definitely be made after pathologic examination. 

Biopsy procedures include needle biopsy or an incisional (surgical) biopsy. The material is examined under the microscope in order to arrive at a diagnosis of cancer.

Microscopic examination is however only the first step in the modern diagnosis of cancer.

A full pathologic diagnosis requires the determination of many aspects of tumor biology including subtypes of particular cancers as as determined by tissue markers, receptors for various growth factors relevant to the potential progression of cancer growth, mutations that may be present in the cancerous cells that may be targets for specific types of treatment, as well as being of prognostic importance.

The reaction of the normal surrounding tissues as well as the reaction of the body’s own immune cells which are often present within the tumor, but which may be blocked in their ability to deal with the malignancy are additional determinants that may well influence the subsequent choice of treatment.

Investigation of these factors involves both immunohistology as well as genetic sequencing where appropriate and may take some additional days in order to obtain the full picture. Once a diagnosis of cancer has been established the next step is to establish the extent of the tumor, a process called staging.

This will usually involve X-rays and scans of additional areas other than the local investigations that were probably done prior to the establishment of the diagnosis of cancer. Patients may often become anxious about the stage but it is important to realize that from the medical point of view Stage is merely a shorthand notation of the extent of the cancer,  important mainly for decisions about the appropriateness of the treatment method/s to be used and only one factor, amongst many others, that determine prognosis.

For localized cancers,  adequate local treatment of the primary tumor remains a cornerstone of treatment. Such local treatment may be accomplished by surgery ( the province  of the surgical oncologist) or by means of radiation therapy ( the province of the radiation oncologist) .

However, for many cancers, even when localized to the primary site and/or the regional lymph nodes additional systemic treatment may be advised for optimal outcomes.

By systemic treatment is meant therapy that is effective throughout the whole body, eliminating or controlling cancer cells that may be present at a distance from the primary tumor but not as yet overtly present or for those instances where cancer is known to have spread beyond the primary site and where local approaches may be limited to a biopsy diagnosis or where local symptoms of the primary tumor such as obstruction, pressure effects or bleeding require some measure of local intervention.  

The assessment of and the systemic treatment of cancer is largely the province of the Medical Oncologist, who needs to consider not only the cancer and its effects on the body as a whole but also to be able to , by virtue of his or her specialist medical training, to assess the impact of such therapy not only on the cancer itself but also on the rest of the bodily organs and functions and to provide an integrated treatment plan taking all these considerations into account. 

Systemic treatment of cancer thus forms an integral part of cancer treatment, either as an adjunct to local treatment ( adjuvant therapy)  or as the primary treatment modality, depending on the particular circumstances or that individual patient's cancer,    and may be considered under a number of headings including;

A relatively newer form of treatment where the systemic treatment is given after biopsy diagnosis but before any definitive local therapy is attempted.

A major consideration, here , when such therapy was introduced was to shrink tumors, making local therapy either feasible or to be less extensive ( a particular example is in the case of breast cancer, allowing more women to be able to undergo breast-conserving, mastectomy-sparing, and treatment). This principle is now also being extended to other types of cancer.

In some specific instances, neoadjuvant therapy has been shown to make deferral of any further local treatment possible ( usually for specific tumor types with specific pathologic markers, including a rebiopsy-confirmed complete pathologic remission of the tumor), without compromising of the ultimate curability of the tumor. When such decisions are to be made regarding neoadjuvant therapy the close involvement of a multidisciplinary team is of vital importance

Here systemic therapy is given following definitive local treatment, which treatment may still, however , leave a residual risk of later relapse, depending on factors such as the type and other specific characteristics of that particular tumor. Adjuvant ( as well as , in terms of later relapse risk , neoadjuvant therapy )  is a major factor in the increased cure rates for a number of cancer types over the last 40 years or so.

Primary Systemic Therapy.
First introduced mainly for the treatment of Hematologic malignancies such as Leukemias, Lymphomas and Multiple Myeloma where the nature of  the tumor is such as to be widespread at first diagnosis and where such treatment registered its first successes,systemic therapy of cancer has,  during my tenure in this field of medicine, become an increasingly important field of treatment for other cancer types of extensive stage, particularly with the advent of a monoclonal antibody, targeted and immune-based therapies, significantly improving the life expectancy as well as the quality of that life for such patients.

   The  different types of  systemic cancer therapies include

1. Chemotherapy
2. Monoclonal Antibody treatments
3. Targeted Therapies
4. Immune Checkpoint inhibitor (ICI) based therapies
5. Pro -Apoptotic therapies
6. High Dose Chemo with Stem Cell Rescue ( autologous or allogeneic stem cells)
7. CAR-T ( Chimeric Antigen Receptor, T- lymphocyte based treatment)
8. Bispecific Antibody based therapy ( engaging autologous T-cells to react against cancer cells via a  receptor/antigen link by means of a monoclonal antibody  engineered to have one arm specific for an antigen on the tumor cell and the other to link to immune activation sites on immune effector cells such as T-lymphocytes or Natural Killer (NK) cells).

The role of the medical oncologist includes not only the administration of  systemic cancer treatment but to educate and to advise the patient with cancer about the various treatment options as well as to ensure that a full and proper medical evaluation of the suitability of the individual patient to undergo these various treatments is in place and only then to advise on the best course of treatment for that person taking into account also of expressed wishes of the patient .  

All antibody production starts with the recognition by B-lymphocytes, the precursors of mature antibody producing cells, of an antigen and even more narrowly defined of an epitope , a smaller, specific, part or region of the antigen.

The basic structure of the antibody molecule is that it is roughly Y-shaped protein molecule made up of a series of amino acids ( coded for by the codon sequences of the respective  immunoglobulin genes in a distinct pattern for the heavy and light chains which in turn consist of constant constant regions, making up the bulk of the molecule, and a variable region consisting of some 110 amino acid sequences of both the  heavy and the  light chains.

Variability in these regions  is what allows for antibody specificity and  recognition of different antigens.This variability is built in by variation (mutation), via a rapid and random rearrangement in the  immunoglobulin producing area of these genes which  are present in an actively expressed format only in B-lymphocytes  as they develop in the bone marrow, which they then exit.

B-lymphocytes that have developed to this point  bear on their surfaces an immunoglobulin structure which has been generated internally without reference to any particular antigen.

This  virgin B-cell then circulates in the blood and through areas, mainly in lymph nodes, but also other lymphoid  structures, where cells termed antigen presenting cells, which have ingested foreign organisms , proteins or parts thereof now come to display parts of these ,  now termed antigens, on their surface. If a B-cell bearing a potential antibody structure which corresponds to this antigen encounters and interacts with   the antigen presenting cell this  triggers further development of that B-cell  ultimately leading it to re-enter the bone marrow  and to develop into a plasma cell which can then in turn secrete that immunoglobulin structure as a soluble circulating antibody. 

The only difference between free  circulating antibodies and the cell bound structure from which it originated lies in the stem end which can be cleaved to free the antibody to circulate independently of the originating cell.

The utility of this mechanism is that it allows for a continuous generation of potential antibody producing cells owing to a rapid and continuous generation of new B-lymphocytes that are pre-made to meet their potential antigens . Those cells which do not encounter a corresponding antigen do not develop further  and are eliminated.

In the normal course of events when such a foreign  antigen is  recognised numerous different B-cells will recognise different epitopes ( which are different short sequences  ) of the same   recognised antigen. The triggered B-cells that have recognised a particular epitopes  do not only turn into plasma cells as described previously  but are also triggered to proliferate before becoming mature plasma cells as described thus forming a clone of cells for each individual B-lymphocyte so triggered.

The aggregate number of such clones , each triggered by different epitopes of the same antigen, is the  polyclonal antibody response that normally occurs in the course of events such as response to infection.

The ability to select cells of only one clone with specificity for a single epitope and to expand such antibody production on a large scale is what underlies the development of monoclonal antibody therapy, which at the beginnings of this technology came to be hailed as the ” magic bullet”.Production of monoclonal antibodies  was first made possible by the introduction of cell-hybrid technology , utilizing the fusion of two distinct cells into one. 

One of the cells being derived from a  cultured  mouse myeloma cell line which has the machinery for antibody production and the other from B -lymphoid cells  derived from the spleens of animals ( initially, often rabbits) vaccinated against a particular antigen which supplies the genetic blueprint for continued production of  specific antibodies  to the  epitopes of the antigen  which that single cell is capable of producing.

Large numbers of such hybrids were generated simultaneously by the admixture of the two cell types, making them fuse  and the growing out the fused cells in tissue culture. Monoclonality was achieved by selection of individual  hybrids which could be   grown continuously ( and further expanded in numbers from a single hybrid cell)   because of the property of the myeloma cell line ( retained in the hybrid cell ) to be able to continuously propagate. 

Further steps are then to isolate and purify, from the culture fluid into which it was secreted ,the  monoclonal antibody. At first only relatively small amounts of monoclonal antibodies were produced but advances in large scale  tissue culture systems allowed for production of such monoclonal antibodies in amounts required for therapeutic use.

Important features that determine fitness for therapeutic use of monoclonal antibody are;  Selection of particular antigens that are either specific to or at least preferentially expressed on cancer cells in higher concentration than on normal cells.  

Exposure ( vaccination ) of B-lymphoid cells to the antigen/epitopes in question to derive the starting point/cell to an  epitope of the antigen  in question.  Selection of an antibody that has  functional effects   by virtue of binding, to the specific   epitope, on  the cancer cells.

These effects may either be  by blocking some sort of receptor,  by binding can cause antibody mediated cytotoxicity ( cell death).

The  separation , purification and stabilization of the monoclonal antibody so that it will retain its functional characteristics after it is produced by the hybrid cell line.  

Hybrid technology is no longer confined to mouse and rabbit cells but can include other cell types. 

Other techniques such as  molecular transfer and insertion of the portion of the DNA coding for a particular antibody specificity directly  into cell lines or even into bacteria have further  expanded the possible  production methods for monoclonal antibodies.

However the  principles guiding the  selection, remain the cornerstone of monoclonal antibody based therapy.Therapeutic success was first demonstrated against malignant B -lymphocytic tumors with  the use of the monoclonal antibody rituximab ( a mouse hybrid based monoclonal antibody) which interacts with an antigen designated CD 20 .

This target antigen is  expressed on a wide  range of B-lymphoid cells, both non malignant and malignant,  and at various stages of their development, is overexpressed in B-lymphoid malignancies.

Use of rituximab results in antibody-mediated cytotoxicity in its own right as well as enhancing the effects of chemotherapy on the malignant cells ( a synergistic action),  resulting in better response rates as well as more prolonged survival of patients with B-cell malignancy treated with a combined chemotherapy + rituximab regimen as compared to those treated with chemo alone.

Subsequent developments in this area include the introduction of obinutuzumab, a humanized monoclonal antibody also directed against CD 20 but at a somewhat  different epitope.

There is an also a monoclonal anti- CD 20 antibody which can be  conjugated to a radioisotope for enhanced  activity against malignant cells dearing CD 20, but its use has not taken off to the same extent as combined rituximab + chemotherapyPolatuzumab and Brentuximab are monoclonal antibodies for use in different  lymphomas, mainly Hodgkin's Disease directed against a different antigen, CD 30 which is expressed in these conditions.

Both these are also available as  antibody -cytotoxin conjugates, about which further below .

In the field of hematopoietic tumors there is also Gemtuzumab ozogamicin , directed against CD 33 present on malignant cells of  the myeloid cell lineage in acute myeloid leukemia.Daratumumab is used for treatment of multiple myeloma and is directed against CD 38 expressed particularly on plasma cells in this condition.

In breast cancer, specifically in  a subtype  known as HER2 positive breast cancer , which has  a tendency to early relapse as well as relative resistance to chemotherapy  the introduction of Trastuzumab ( and later Pertuzumab) in addition to chemotherapy helped, first, to overcome the relative chemo resistance of these tumors. 

 As  adjuvant and/ or neoadjuvant treatment along with chemotherapy for earlier stages of Her 2 positive breast cancer , the addition of these monoclonal antibodies  is  effective in lowering  the higher risk of early relapse.Gastrointestinal, renal and lower urinary tract ( including  prostate cancers have also been fruitful areas for monoclonal antibody research and  treatment .

Cetuximab, Panitumumab ( both targeting the epidermal growth factor receptor , EFGR)  Bevacizumab ( targeted against tumor vasculature) as well has Trastuzumab  ( when HER2 expression has been found in  certain gastrointestinal cancers) are examples.

In urologic cancers a  monoclonal antibody against prostate specific membrane antigen( PSMA)  linked to a radioisotope for delivery of radiation to metastatic prostatic carcinoma cells is proving to be effective when these tumors are no longer responsive to hormone manipulation.

The above examples are not meant to be an exhaustive list but  rather to be  illustrative of the range of cancers where monoclonal antibody treatment is playing a role.

The use of Bevacizumab deserves to be expanded upon since here the target is not the cancer cell per se but to modify the supporting stroma of the tumor, mainly in the treatment of colonic cancer.  

Cancerous tumors need a blood supply in order to continue to grow . Such tumor vascularisation comes about through the action of Vascular Endothelial Growth Factor ( VGF ) , elaborated either by the tumor itself or by the tumor cells influencing other stromal cells to secrete this growth factor that then interacts with the corresponding receptor ( VGFR) on endothelial cells of blood vessels inducing them to proliferate and to grow into blood vessels that will feed the cancer.

Blockade of blood vessel proliferation slows down and influences tumor growth in a number of ways, including making the cancerous cells more susceptible to chemotherapy.

A more recent extension of monoclonal antibody treatment has been the development of antibody-drug conjugates, already alluded to above. These conjugates are produced by  the chemical linkage of a monoclonal antibody  to a cytotoxin .

After  administration of the conjugate  the antibody portion  can link to its target ( receptor or antigen)  and the whole receptor-antibody-cytotoxin complex is internalized. ( something that is a part of certain  receptor ligand interactions, where the attachment of the antibody to the receptor substitutes for receptor ligand interaction) and then  the cytotoxin is released into the interior of the malignant cell by hydrolytic enzymes which are present in the cell cytoplasm.

The cytotoxins, which are basically chemotherapeutic agents  of various types ,but highly potent and toxic at minute concentration are selectively delivered to the tumor cells . 

There is however some degree of escape and these drug conjugates can be associated with a range of side effects not encountered with the usual run of chemotherapies. 

Examples include; Trastuzumab emtansine and  Trastuzumab deruxtecan  for HER2 expressing breast cancerBrentuximab and Polatuzumab Vedotin for CD 30 expressing lymphomas Sacituzumab Govitecan for HER 2 negative breast cancers as well as for lung cancers.

Belantomab mafodotin directed against the B-cell maturation antigen ( BCMA) and conjugated with auristatin for multiple myeloma 

What should  be evident from the discussion of selection of  monoclonal antibodies by their reactivity against specific epitopes and the listing of those epitopes, is that the specific antigen has to be present for the antibody  to be therapeutically active and this needs,in the vast majority of instances to be tested for.

This testing can be by means of histochemical/histopathological investigations which also involve the use of monoclonal antibodies( with  the same or similar specificity as the therapeutic ones), linked to cytologic dyes which can then be detected as cell staining under the microscope.

 Alternative or confirmatory methods of detection include molecular biological methods that can detect and amplify RNA that is responsible for the synthesis of the particular protein that constitutes the antigen. 

Having said all this one should point out that although a major advance, monoclonal antibody therapy is not uniformly successful and/ or that after initial success the tumor may evade such treatment by antigen shedding, cloaking or further mutation altering the epitope against which the monoclonal is directed.

Not fully a “magic bullet “ but rather a silver one in the sense of being a directed treatment against a highly specific target rather than a shotgun.  With established benefits, monoclonal antibody therapy will no doubt be amenable to further expansion of its effectiveness against cancers. 

In comparison with monoclonal antibodies which target receptors and molecules expressed on the external surface of the cancer cell , small molecule targeted therapy comprises a relatively new class of anticancer drugs which are small enough to penetrate or be absorbed through the cell membrane and to exert their effects on intracellular targets.  All cells, including cancer cells utilize signaling pathways to control cellular functions , including cell growth and proliferation . 

Signaling pathways interact to produce   both positive and negative  feedback loops. These pathways consist of the signal/ligand, the receptor/transducer and  secondary messengers within the cell.

Common ligands are growth factors and certain hormones that act at the level of the cell membranes.The receptors themselves,  often undergo dimerisation and  a change in shape on ligand binding and this  acts as a  signal transducer activating intracellular messenger pathways that themselves  consist of a series of messenger proteins that transmit , modulate and integrate signals from different sources.

These in turn lead to the cell nucleus , where they  interact with intranuclear  proteins that ultimately  result in transcription and translation  of genes to produce proteins which are the structural and functional units of the cell .  These systems  allow cells to respond to changes in the cellular environment in a coordinated manner . 

The signaling pathways thus  link stimuli from outside to effector mechanisms within the cell.   A fundamental defect found in cancer cancer cells is dysregulation of these feedback control loops resulting in the propensity of cancer cells to continue to grow in an uncontrolled manner .

This may occur either because of overexpression and/or mutations of the growth controlling receptor/s and/or the second messenger pathways.

Many of such receptors have what is called kinase activity , which converts the  conformational change generated by the attachment of growth factor to the receptor to a chemical signal generated at an internal  portion of the receptor. 

This chemical signal,from the internal domain of the receptor  involves  the release of phosphorylated  energy carrying molecules by activation of tyrosine kinases (TK’s) . 

The message   is then carried further by the activation  second messengers , which in turn, may also be overexpressed or mutated in cancerous cells kinases are of various types and can be inhibited by small synthetic molecules which can  attach to their active sites thus inhibiting or aborting their activity.They include the tyrosine kinases associated with the internal domains of growth factor receptors of the broad Epidermal Growth Factor Receptor class .

There are 4 distinct classes  of EGFR/erB, 1-4 receptors , which are of importance in a variety of  tumor  types.The first of these is the erB1 receptor class which is important in hematopoietic cells.  The  mutated form of this receptor  is  the product of a specific chromosomal  mutation, the Ph chromosome. 

This is  a shortened chromosome resulting from a reciprocal translocation of genetic material between chromosomes 9 and 22 in somatic stem or very early progenitor cells of the hematopoietic system.The Ph chromosome mutation was first detected  by chromosomal mapping and can now be detected  by molecular biologic  polymerase chain reaction ( PCR) methods  . 

The affected region is  named the  BCR - ( breakpoint cluster region)Abelson fusion gene, which when translated generates a fusion protein of the erB1 class of  receptor  molecules in the affected  hematopoietic stem cells. 

The abnormal receptor is constitutionally active and drives the proliferation of a clone of affected  hematopoietic cells resulting in the disease known as  chronic myeloid leukemia ( CML) and in some Ph positive acute lymphoblastic leukemias.  

Imatinib was  the first example of  a new class of chemical compounds the  tyrosine kinase inhibitors (TKI’s) to have been developed for treatment  of this condition and was the archetype of small molecule target inhibitors.

Imatinib inhibits constitutive TK activation by binding to the adenosine triphosphate (ATP) binding site on tyrosine residues of the internal domain  of the BCR-Ableson protein.

Preventing this protein phosphorylation locks the protein in a closed or self inhibited confirmation.

Imatinib revolutionized the treatment of CML by providing an alternative to treatment options which were previously restricted to symptomatic suppressive therapy with little change to the ultimate outcome of the disease  and to allogeneic bone marrow transplantation when this was feasible.

Now a treatment which specifically targeted the malignant clone was available and able to suppress the proliferation of the BCR /Ableson positive cells the disappearance of which could be monitored of the cells, from blood and bone marrow which carried the hallmark gene abnormality.

Imatinib was later found to be active against other tyrosine kinases of  CSF 1r, cKit , Flt3 and PDGFR related kinases in conditions such as hypereosinophilic syndromes and leukemias, gastrointestinal stromal tumors and systemic mastocytosis. 

Inhibition  of the activity of other  members of the  EGFR /erB class of receptors, which are  widely expressed in a range of cancers of varied  origin, are the descendants of this first small molecule inhibitor. class of drugs which all may be seen as stabilizers of the genetic dysregulation induced  along the pathway to cancer development  .

Eleven ligands have been identified as being able to interact with and to stimulate growth of cells bearing receptors of the EGFR class and while there are monoclonal antibodies , which can block ligand- receptor interactions the use of monoclonal antibodies alone to cause EGFR blockade has often been disappointing.

The problem in cancer  is not only a matter of ligand/receptor interaction but of more complicated  dysregulation of cellular functions that occur in cancer and  induced by multiple mutations within the cancer cell.  The class  of small molecule inhibitors  may be seen as stabilizers of such dysregulation caused  by some of these mutations  which can cause interaction of the mutated receptor  with more than one ligand and/or result in ligand independent activation of  the  signaling pathways, which would not be blocked by monoclonal antibody binding to the external receptor domain.  

Other small molecule tyrosine kinase inhibitors   which exert  their   therapeutic actions at the internal domain of these receptors have been developed These include  lapatinib for the erB2/Her2  class of receptors, which are  most commonly found overexpressed in a subset of breast cancers ( called HER2+ breast cancer,  and which accounts for between 15-20% of all breast cancers),  combined blockade by monoclonal antibodies directed against the external domain together with small molecule targeted therapy is more effective than monotherapy. 

HER 2 positivity is not confined to breast cancer alone but is found, albeit at a lower  percentage, in other cancers such as gastrointestinal cancers of various types as well as in a small number of lung cancers. Such findings are beginning to  lead to the introduction of what is called tumor agnostic treatment , where the target is not the particular histopathological type of cancer but rather the molecular biology or molecular  drivers of cancer cell proliferation.

A large number of different kinase inhibitors have been developed, either chemically distinct or tweaked molecules , adapted for the different kinases.

Some of the tweaked molecules show differences mainly in terms of side effect profiles rather than efficacy whereas others do show  differences in efficacy or at least may be active when previously effective inhibitors have lost efficacy because of further mutation within the cancerous cell of which more below. 

Such targeted treatments may be used both before ( neoadjuvant) or after (adjuvant) local treatment or for primary treatment of more advanced stages of disease.Another class of signals controlling cell function and growth  originating from the cell membrane is the MAPkinase -  Phosphoinositol ( PI-3K ) pathway , which in one branch  connects via protein kinase C  to   activation of transcription factor NF-kB and in another branch to the mTor pathway .

Small molecule inhibitors of the PI-3k  signaling pathway have  been developed and are in use while  others are under investigation.

Activation signals for each of these pathways  are  transmitted to the cell nucleus  by a series of second messengers which not only transmit but also modulate and integrate these messages.

These secondary messengers, themselves proteins,and  which  may also be mutated in cancerous cells, are also potential targets for treatment.  Therapeutic small molecule targeted treatments do include drugs that interact directly with secondary messengers such as mutated  raf and ras proteins. 

Inhibitors of mutated Braf proteins  have substantial response rates in malignant melanomas  that bear a specific mutation in their genetic code for Braf, particularly when combined with MEK inhibitors ( where MEK signaling can come to constitute an alternative signaling pathway when raf signaling is inhibited. 

Braf mutations also do occur in some cases of colonic cancer and the use of Braf inhibitors is being explored in these patients.

Mutations of ras  are even more common than raf mutations and indeed ras is one of the most common signaling pathway mutations occurring across a number of different cancers including colonic and lung cancers. 

Ras mutations are responsible for signal pathway  activation in a ligand independent fashion and the presence of a ras mutation is both prognostic for more aggressive tumor behavior as well as predictive of failure of response to treatment directed against the external domain of EGFR  by means of monoclonal antibody therapy, since ras mutation signaling bypasses the ligand- receptor interaction step .

Small molecule targeted treatments  are numerous and diverse and defy classification into simple schemes.  Well over 100 such drugs are now available and now include not only the pathways discussed above for solid tumors but also mutations in pathways involved in hematopoietic malignancies such as B-cell lymphomas and leukemias by Bruton Tyrosine Kinase inhibitors ( BTK I’s). 

In classic hormone signaling related pathways such as the estrogen receptor pathway in hormone sensitive breast cancer breast  with the development of selective estrogen receptor degraders ( SERDS) and cyclin dependent kinase inhibitors ( CDK inhibitors) which inhibit the proliferation of cells by blocking entry into the proliferative phase of the cell cycle induced by the exposure  to estrogen . 

Other examples of targeted treatments include vorinostat , which inhibits  histone deacetylation  as well as  methylation inhibitors which change the epigenetic landscape of  tumor cells, altering gene expression , even of mutated genes , by changing their ability to be expressed via proteins that are part of the outer structure of  chromosomes  but  not part of the  DNA  itself, hence epigenetics well as inhibitors of DNA repair  enzymes. 

The first examples of this latter class of molecules being  inhibitors of poly- ADP- ribose polymerase ( PARP), an enzyme involved in repair of DNA damage as part of the wear and tear process that all cells may be subject to If repair can be effected the cell goes back to bring a functional one but if damage is extreme and cannot be repaired effectively the cell is shunted to undergo cell death by an internal process of apoptosis ( meaning withering  ) by triggering a series of caspases that result in a cessation of various metabolic functions.  

In normal cells  BRCA1 and BRCA 2  proteins, products of the BRCA genes,  assist with DNA repair. People with inherited , or germline , BRCA mutations (mostly women who develop either breast and/or ovarian cancer at much higher rates than found amongst women without such mutations ) or in cancer cells that have acquired such  mutated BRCA genes as part of the cancer development process  and hence have abnormal  BRCA proteins this DNA repair mechanism is deficient or weakened allowing for further mutations to accumulate.

Inhibition of PARP in such cells amplifies and speeds up this process of DNA damage to an extent that even cancer cells which can continue to proliferate in the presence of mutational and other forms of DNA damage accumulate damage to a degree which even they cannot tolerate and thus undergo apoptosis.     

From what has been discussed above some general concepts do start to emerge regarding targeted treatment. These are; There must be a targetable mutation dectable. The target should ideally remain stable.The target must be druggable The first of these requirements will probably turn out to be true of most cancersThe second means that cancers will need to be much more extensively investigated than by mere examination under the microscope in order to learn about which drivers are present. 

While some of these investigations can be done by means of  immunohistochemical investigations and are part of the routine of evaluating certain tumors ( such as Estrogen Receptor and HER2 status in breast cancer) most of the investigations required prior to targeted treatment decisions require molecular biological techniques .There is already a large disparity in cancer treatment  between affluent and less affluent and less developed  societies based on costs and this will be exacerbated when the costs of such investigations are included. 

The boasts that the costs of genetic sequencing have now become such that it is within easy reach is certainly not true in a fee for service model where costs remain considerable even when there is access to automated investigation because of  costs of often patented primers and other parts of the methodologies used, including the AI programs used to interpret sequencing results.  

Other models , perhaps by having a pool for costs underwritten by manufacturers of targeted drugs for the diagnostics required, may be a way forward. However this will require a concerted and inclusive model since some individual  manufacturers' attempts appear more in the nature of a lotto , helping to sell their own drugs by subsidizing the costs of the  companion diagnostics but only for those that are  positive and linked to  the purchase said drug , particularly when the frequency of a positive test is low.

The third issue, that of stability of the target speaks to the issue of the stabilization of the dysregulation of signaling that occurs in cancer that has been alluded to earlier. There is considerable variation in duration of response to targeted treatment between different cancers and even between the different patients with the same cancer and the same target ( are least as far as we can now detect with the routine investigations that are done to assign a patient to a targeted  treatment category. 

Some of this may be because of treatment compliance issues, which must always be assessed by the oncologist and which could be addressed by judicious switching of medications as the side effects of different agents targeting the same pathway may be different but it must be pointed out that in the main not only does treatment schedule have to be maintained in the long term a time does come in most instances where further mutations in the cancer arise , making previously effective therapy to no longer be so. 

The last issue, that of druggability remains, either because some targets are still unknown  ( an issue of finding new targets ) or because no drugs are available for a mutation that has been found ( an issue of drug discovery).

The target issue can be illustrated by considering the   frequency of occurrence  of potentially targetable mutations  for lung cancer by findings in various population groups. This shows that among people of Asian descent just over 80% have a targetable mutation ( with over 60% of these being an EGFR mutation whereas for those of African origin  only 50% have targetable mutation ( with EGFR mutations being present in only 30% of these).In people of European ancestry, the corresponding figures are 65 %  targetable with about 45% EGFR related. 

Whether these differences reflect differences in causality or of population genetics is at present unknown. 

Most likely it is a combination of the two.For treatment of these targetable lesions in lung cancer  nine different classes of targeted drugs are available  with obviously the EGFR targeting agents to the fore and with many different  individual molecules in this group, including older agents as well as newer ones , some of which have advantages for individual clinical circumstances such as location of metastases or which may work when a previously active agent ceases to be so, either or both. 

Targets other than EGFR mutations are rarer , accounting, individually, for between 1 -9% of potentially targetable lesions, each with a different target and drug or drugs but generally with fewer available medications  ( often only one single option for the particular, non EGFR class,  target).   Whether some of the targeted  therapies  such as PARP inhibitor therapy will turn out to have long term adverse consequences is not known. 

Only a limited number of studies of ovarian cancer with BRCA mutations that show survival benefit have been reported .  

Caution should be exercised particularly in treatment of those with germline BRCA mutations where further reduction in  cell repair processes in other normal tissues may become an issue . 

While it is not  fully known why  breast and ovarian tissues bear the brunt of the increased propensity for tumor development there are a number of other cancers which are more prevalent in BRCA mutation carriers and long term survival based on an all causes analysis  rather than ovarian or breast cancer  survival data data are needed.

Some cancers depend on normal hormonal stimuli for their growth . 

These cancerous cells not only have but may well overexpress  receptors for a hormone such as estrogen or testosterone. 

The best known examples of endocrine responsive (or potentially responsive) tumors are breast and prostate cancers. 

Such endocrine responsive tumors are characterized by ( in the case of breast cancer ) by detection of the specific estrogen receptor by staining for the receptor on histopathologic examination of a tumor sample. Estrogen receptor is  a test which, among others, is mandated for in all cases breast cancer, since it defines a type of breast cancer ( hormone receptor( HR) positive) which not only has prognostic but also therapeutic implications. For this type of breast cancer the initial systemic treatment , be it in the adjuvant/neoadjuvant or more widespread disease setting, should be  by means of hormone manipulation.  Such hormone manipulation may be done either by reducing the production of estrogen, by blocking the attachment of estrogen to the receptor or  by direct manipulation of  the receptor usually involving its degradation. The proportion of HR positive breast cancers rises with increasing age from about 30% in the premenopausal age group ,but  by age 70 up to 70% of women with breast cancer have an  HR+ tumor.In the case of prostate cancer , While there are pointers to the likelihood of the tumor being HR positive such as cytologic grade , routine assay  of the tumor for testosterone receptor (TR) is not performed because it is technically more difficult but also because,  at least initially, virtually all prostate cancers are hormone responsive. The same principles for treatment by hormonal manipulation i.e. reduction of hormone levels or blocking their interaction with the receptor apply, both as  treatment  in the adjuvant and in the more advanced disease setting.

Based initially on two simple ideas , 1. That more chemotherapy will kill more tumor cells and  2. that the dose limiting toxicity , at least for some selected chemotherapy agents is hematological toxicity  , that can be overcome by the provision of normal hematopoietic stem cells that have not been exposed to the chemotherapy agent.

These ideas have undergone some modification along the way but are still the underpinnings of this form of therapy. The Stem Cell Rescue or Support part can be divided into Autologous ( that is that own persons) and Allogeneic ( from another individual) hematopoietic stem rescue. Used quite extensively from the 1960’s onwards to the early part of this millennium this form of treatment is being eclipsed by other therapeutic options for cancer treatment, which were not available then. 

There are however residual indications for high dose chemotherapy. Schedules and regimens for high dose therapy with autologous hematopoietic  support  are rarely completely ablative for bone marrow stem cells but do cause very prolonged suppression of normal hematopoiesis , thus increasing the risk of anemia ,infection and bleeding , which can  be overcome by collecting stem cells ( initially from the bone marrow itself and later and even more successfully by apheresis and of such stem cells induced to migrate into the blood compartment under the influence of hematopoietic growth factors  ), these cells  would be collected and stored for use before giving the high dose chemotherapy and administered only after the chemo drugs have  been eliminated from the body.  

This allows for shortening of the period of hematopoietic suppression from weeks, with an increasing risk of the  complications described , to days with correspondingly lesser risks and often even  allowing these procedures to be done on a largely home based  care program. High dose chemotherapy with autologous support remains indicated as an option for  consolidation therapy after initial chemotherapy  ( particularly when there has been a good ( complete ) clinical response to the  initial chemotherapy .

Consolidation treatment with HDC remains an option which has been  shown to prolong such remissions for a number of lymphomas , leukemias and in  multiple myeloma but without giving a guarantee of a cure. The length of such remissions can be predicted on the amount of residual disease. When this is absent ,or at least undetectable by the most sensitive methods available  it will be longer, on average,  than when residual tumor cells are detected.The place of HDC in these situations would need to be discussed with the patient in the light of some emerging maintenance  or initial  induction with some of the targeted  treatment options for  these conditions. 

High dose chemotherapy with Allogeneic  Stem cell transplantation is still an option for some hematopoietic tumor such as acute leukemias and it is now known that a major part of the long term remission benefit that is achieved by such treatment is because of immunological differences between donor and host tissues resulting in a graft versus leukemia effect by the immune reaction of donor derived lymphocytes acting against residual leukemic cells of the host and which are now perceived by the reconstituting/reconstituted  immune system to be foreign.This graft versus leukemia effect is based on chimerism ( two different  cell populations in the same body)  and can be boosted by additional donor lymphocyte infusion.

The major functions of the immune system are to detect (recognise) components termed antigens on the surface of foreign organisms or cancers by  a class of antigen processing and antigen presenting cells   and to destroy such  foreign invaders or abnormal cells including cancers. 

In regard to cancerous cells, this function  is termed immune surveillance and is thought to be a major part of  the evolution of  the immune system.

Immune reactions are divided into classes that include both antibody production (involving B-lymphocytes ) and cellular immunity (involving T-lymphocytes).

For the purposes of immune surveillance and destruction of both potential and actual cancers T-cell immunity is of primary importance as cytotoxic  T-lymphocytes can both engage with and destroy such cells by direct contact between the immune and the malignant cell or by secretion such as perforins and other cytotoxic substances by the activated T-cell.  

This process involves recognition of abnormal cells by virtue of these displaying new antigens ( neo-antigens , cancer related antigens ) not present on normal cells, or antigens present in much higher concentration on malignant cells as compared to their normal (non-cancerous counterparts), collectively termed tumor associated antigens ( TAA’s) . 

Following antigen recognition  by the T-cells,  triggering of these cells to both  expand in numbers and to proceed to destroy the specific antigen bearing cells or organisms is mediated  by endogenous chemical mediators of the interleukin system,with Interleukin 2 playing a pivotal role in the start of T-cell activation . Initial  Interleukin 2 secretion  is mainly  mainly from macrophages (scavenger cells ) , leukocytes  and vascular endothelial (lining ) cells  all of which , while not being defined as cells of the adaptive immune system, are nevertheless part of host defense mechanisms and can recognise the presence of foreign invaders .

While immune surveillance is a powerful mechanism for destruction of cancer cells at a microscopic level when tumors are composed of limited numbers of malignant cells, without an established stromal structure of supporting cells, which are not in themselves cancerous but derived from normal host cells and  which have been co-opted by the malignant cell to form the tumor microenvironment.

Once this microenvironment has formed it influences antitumor immunity by the release of cytokines and other mediators of chronic inflammation which have a negative effect on anti-cancer T-cell immunity.

The opportunity for immune surveillance as a mechanism protecting against cancer development into a disease state is probably of  limited in terms of both numbers of cancer cells in relation to cytotoxic T-cells deployed  in  the local area of the tumor   as well as the time frame before brakes that limit the scope of the T-cell  immune reaction come  into effect    . 

Once cancer has occurred to the point where it is a clinical disease  immune surveillance has been evaded, and  the immune landscape of the tumor differs  with the emphasis being not only immune suppression but indeed sometimes  on a co-option of the immune system to enhance tumor growth, unless the negative regulators of immunity can be counterbalanced and overcome.

The flip side to such favorable immune reactions such  as immune surveillance is the occurrence of auto-immune disease where a dysregulation of the immune system allows for  immune destruction of normal cells and tissues as a consequence abnormal and prolonged immune responses. Immune activation needs  to stop as well as to start.

In order to understand how the immune system can be re-engaged to exert its anti-cancer effects one needs to understand more about immune regulation.Immunity is a tightly regulated process that not only involves  activation but also control and inhibition mediated both by regulatory cells (T-Regs, or T- regulatory cells) as well as by interactions between additional molecules, other than the primary antigen that trigger the immune response and  that act as  either co-stimulators or inhibitors .ICI therapy is predicated on the notion that some of the endogenous T-cells present in the  

cancer sufferer have recognised and could potentially mount an immune response to the cancer cell but are inhibited from doing so by the Immune Checkpoint Inhibitory (ICI) systems that are described in more detail below and can either  be re-engaged or induced anew  for  this function. Two major checkpoint inhibitory systems have been studied in a fair amount of detail.

The first is the CTLA-4 system , which acts as a brake on T-cell immunity early on during the activation phase, and the second the PD1/PDL1 ( where PD stands for programmed death and PDL1 for programmed death ligand ) system  which inhibits later phases of T-cell cytotoxicity . 

Engagement of the CTLA-4 system abrogates the T-cell immune response in its early phases  ,while engagement of the PD/PDL1 system either by blocking PD1, the receptor,   or by blocking PDL1, the corresponding ligand, results in what may be seen as a suspension of the immune response which can nevertheless , under certain circumstances, be reversed.T-cell inhibition may be brought about  by regulatory cells, a switch to chronic inflammation which involves blood and tissue macrophages as well as a change in amount and type of interleukins secreted as well as by cancer cells themselves or through interaction directly with T-cells and/or non cancerous cells ( the stromal cells ) found within cancerous tissue. 

Monoclonal antibodies which block the activation of the receptors present on the T-lymphocyte  for  immune checkpoint activation have been developed and  were   one of the first consistently active  steps in the  long desired and anticipated  engagement of the immune system as a treatment for cancer apart from the graft versus cancer effect described earlier .There is one example of an ICI ,  

CTLA-4 inhibitor, available and registered for clinical use, ipilimumab. As single agent treatment its major contribution, so far, has been in the treatment of malignant melanoma, where deep and sustained remissions have been observed in about 30 % of treated patients which is higher than the about 10% response rate for immune stimulation by interleukin 2 infusion and the very  occasional and unpredictable responses from other earlier  attempts at adaptive immunotherapy  . 

A  number of monoclonal antibodies for reversal of PD1/PDL1 checkpoint inhibition are available and others are in the pipeline. These are of one of two types , one blocking PD1 (the receptor)  while the other type blocks  the ligand molecule (PDL1). The presence of PD1 or of PDL1 on cells, be they immune effector or tumor cells can be detected using histochemical staining methods and the presence and degree ( as in percentage of cells showing staining) of staining  is a guide to the likelihood of of a positive response to treatment, although not perfectly so. 

Cut off levels for PD/PDL1 staining that have been found to be significant for at least a  30% chance of response are 10% staining, and 50% staining for significantly higher response rates higher of  than 50% , although other factors such as tumor type, presence or absence of metastases as well as site of metastases seem also to play a role.Alternate predictive tests that have been suggested as a guide to ICI, PD/PDL1directed  therapy response,include tumor mutational burden (TMB , based on an increased likelihood that  cancer cells with a high mutation rate might express more neoantigens ) as well as MSI ( microsatellite instability , high MSI indicating a defect in the ability of cells expressing this , to be able to repair mutated DNA strands ).

From the practical point of view there do not seem to be major differences in clinical efficacy as to whether PD1 or PDL1 inhibitors are chosen for treatment but when assessing the chances of response it is necessary to know and to select on the basis of which staining test ie PD1 or PDL1 staining was performed.Chemotherapy  may be used together with ICI therapy and seems to enhance both the chances as well as the degree of response( with patients with PD/PDL1 expression of as low as 1% benefitting   , but combination treatment does mean exposure to chemo toxicity ,which may well influence the acceptance of , or in frail patients, the feasibility of such combination treatment.   

Combined CTLA -4 together with PD/PDL1 inhibition does, at least in selected tumor types , seem to have higher response rates and longer duration of response, but again at a cost of increased  risk of  immune mediated side effects such as endocrine deficiencies, colitis, pneumonitis and other toxicities resulting from ,off target , immune reactions directed against normal cells and tissues.

Much of what was discussed about the immune system and cancer  under the heading of ICI therapy is applicable to CAR -T therapy which can be seen as an extension of that with the main variables being that with CAR-T the T-cells are intentionally pre- primed for recognition of a single specific TAA as well as being expanded in number outside of the body. Priming for reactivity with the chosen antigen is accomplished by engineering the CD3 / T cell receptor complex on potentially cytotoxic T cells. 

The first step in this process is to  collect T-cells  from the patient's bloodstream by a process of cell apheresis . The collected T-cells are then genetically manipulated in order to express a T - cell receptor with specificity for the chosen antigen by insertion of a coding sequence for the variable light and the heavy chain regions of a monoclonal antibody raised against that  specific  antigen.When expressed on the T-cell surface this antibody fragment can form a bond ( together with self recognition, or MHC , complexes) that lead to initiation of the immune response. 

In order for this recognition  to proceed CD 3 activation , which in turn stimulates IL2 production by the T -cells as previously discussed, takes place to the fullest degree the cells are additionally manipulated to be primed for  CD3 activation at the same time as the antigen receptor portion of the complex is activated. 

This was the formula used for the initial generation of CAR-T , since then further advances include additional engineering to incorporate one or more co-stimulators which can enhance the reactivity of the CAR T-cell as well as helping to maintain its longevity. These manipulations of the collected T-lymphocytes require a highly stable source for  the fragment of the genetic code for the mutations that are to be used by  insertion  into the T-cells , which insertion, in turn, is done by introducing DNA coding portions  into viral vectors which the carry the information to the cells being engineered. 

All this requires  highly complex technology and also  means that , at present, most CAR-T therapy is personalized for a particular patient.

The strength of the antitumor immune reaction is further enhanced by expansion of the engineered T-cells by expansion of their numbers in  tissue culture systems.

These processes were initially carried out in specialized laboratories in research institutes but more recently there are a number of FDA approved commercial concerns to which collected cells may be submitted for engineering and expansion, obviously at a price. 

While theoretically any TAA relevant to any particular cancer may be chosen for the engineering ( and a number of small trials in various cancer types  have  taken place ) in practice and in particularly for the  regulated commercial facilities FDA approval has been given only for CAR-T cells with a limited number of antigenic targets and hence limited types of malignancy , mainly leukemias , lymphomas and multiple myeloma.

The  antigen targets for lymphoid malignancies being mainly CD19 ( a commonly expressed antigen found on a variety of B- lymphoid tumors and BCMA ( B-cell maturation antigen ) , found to be much more highly expressed on the malignant plasma cells of multiple myeloma than on normal bone marrow plasma cells. High response rates and some very prolonged responses have been reported in these conditions treated with CAR-T therapy . 

Major determinants of response appear to be CAR-T dose and CAR-T persistence in the body . Despite the high response rates CAR-T is not universally successful . Inadequate dose,immune cell  distribution and penetration of CAR-T into the tumor as well as suppression of the anti-tumor effects by T-regulatory cells or by stromal factors ,as discussed previously,   antigen loss or masking on the malignant cells as well as loss of (?by host immune cell  removal)  of CAR-T  may all play a role in inadequate response and/or relapse.   

Various methods to enhance the  persistence of engineered CAR -T  are under investigation. Therapeutic outcomes of CAR-T can  be potentiated by the addition of ICI therapy to CAR-T treatment . 

Other cell types such as natural killer (NK) cells and /or tumor infiltrating lymphocytes (TIL’s)  , by virtue of their perceived attraction to the sites of those tumors that have an abundance of such cells have been postulated to be alternative and/or better sources of cells for cancer treatment but this remains to be investigated further. It should also be pointed out that CAR-T and related cell therapies can be associated with a range of immune mediated side effects and sometimes with treatment related death . These potential complications occur with sufficient  frequency (at least at present ) so as to make CAR-T unsuitable for first or even second  line treatment, at least for the moment.

Cost is also likely to remain high and this together with limited availability of slots for such personalized and lengthy ( 4-12 weeks at present ) for the  preparative cell engineering and expansion phases , during which a patient with rapidly progressive and/or extensive malignancy is likely to need some form of bridging treatment  are also likely to limit this form of treatment to selected specialized centers.

An early variation on the theme of immune activation (as opposed to disinhibition, as achieved  by ICI treatment) was the use of IL2 by intravenous infusion to kick start, and /or to maintain anticancer immune reactions. 

This form of therapy was most used for treatment of metastatic malignant melanoma again with potentially severe side effects ( mainly in the form of hypotension , leaky vasculature and pulmonary oedema) which however was manageable and transient and which may still be  something under consideration for selected patients either after or along with other forms of immune treatment for cancer.Bispecific antibodies somr of which may be regarded  as a crossover between Monoclonal antibody  and CAR-T therapies . 

In these instances one the ends of the Y-shaped antibody molecule previously described has specificity against a TAA while the other has specificity for the CD 3 , T-cell receptor activation complex , thus drawing the T-cell and the TAA antigen together and activating the cytotoxic T-cell at the same time.

Examples include ;Blinatumomab for multiple myeloma where the one antibody part  is against  BCMA and the T-cell engager part is directed against the CD 3 complexCatumaxomab an engineered  pairing of  an ovarian cancer specific TAA MoAb( monoclonal   antibody) with  CD3 MoAb  Approval for  Catumaxomab, although originally granted regulatory approval based on an early trial, was subsequently withdrawn by the European Drugs Agency, but the example serves to illustrate the direction of research.

Another approach was with Advantomab a bispecific MoAb with one arm directed against EGFR and the other MET directed, the idea being that drawing together and inhibiting two different receptors in one may be more efficacious.

It is however too early to tell how a   TAA /CD 3  bispecific antibody pairing would compare to CAR-T as there are no comparative trials but if effective would have the advantage of off the shelf treatment and would allow for treatment of larger numbers of patients than could be handled by current CAR -T programs. 
Lastly it should be noted that although specifically targeted immune based treatment has come to stay as a valuable addition to the systemic treatment of cancer there is no proof that any form of dietary supplementation or the use of any so-called “immune boosters” has any benefit for cancer treatment. Indeed as discussed effective harnessing of the immune system for cancer treatment is a matter of highly specific engagement of the immune effectors and cannot be by a nebulous “immune boost” .